Process to prepare pioglitazone via several novel intermediates

ABSTRACT

A novel process for preparing thiazolidinediones, preferably Pioglitazone, as described. Also described are novel intermediates involved in its synthesis and process for their preparation and use in medicine.

This is a divisional of application Ser. No. 10/520,166, filed Oct. 4,2005, now U.S. Pat. No. 7,465,801; which is the U.S. national stageunder 35 U.S.C. 371 of Int'l Application No. PCT/IN2003/000241, filedJul. 15, 2003; the entire contents of which are hereby incorporated byreference in this application.

FIELD OF INVENTION

The present invention relates to a novel process for the production ofvarious pyridine substituted 5-[4-[2-(alkyl substitutedpyridyl)ethoxy]benzyl-2,4-thiazolidinedione derivatives of generalformula 1, and their pharmaceutically acceptable salts. The presentinvention also discloses novel compounds which are suitable asintermediates for the preparation of such thiazolidinediones.

Compounds of formula 1 are known to exhibit hypoglycemic andhypolipidemic activities. The present invention also relates to thenovel intermediates of formula 3, 5, 6, 9, 10(b) 11, 13, 14 (Scheme I,II, III) and their corresponding salts, used either as a racemate or inoptically pure form to prepare compounds of general formula 1. Suchnovel compounds of the present invention can also be suitably formulatedfor treatment of diabetes, hyperlipidemia and obesity or diseases causedby insulin resistance as a pathophysiological mechanism. This invention,in particular, relates to a novel process for the production of5-[4-[2-(5-ethylpyridyl)ethoxy]benzyl-2,4-thiazolidinedione(Pioglitazone hydrochloride, R in 1 is 5-ethyl).

BACKGROUND OF THE INVENTION

The present invention provides a process to prepare various pyridinesubstituted 5-[4-[2-(alkyl substitutedpyridyl)ethoxy]benzyl-2,4-thiazolidinedione derivatives of generalformula 1, and their pharmaceutically acceptable salts. These compoundshave been found to be advantageous for their therapeutic applicationseg. antidiabetic and hypolipidemic, especially as insulin sensitizingagents. Such compounds have been described in patents U.S. Pat. No.4,687,777 and EP 193256. EP 0508740 discloses Pyridine N-oxide analoguesof thiazolidinedione derivatives, including the N-oxide of Pioglitazone(1), having antidiabetic and hypolipidemic activity. U.S. Pat. No.4,444,779 and EP 008203 discloses new thiazolidinedione compounds,including ciglitazone and their pharmaceutically acceptable saltsthereof, which have similar antidiabetic properties.

Diabetes affects a large population and this condition is associatedwith a number of other complications. Usually, the disease is associatedwith other disease conditions such as obesity, hyperlipidemia,hypertension and angina. It is a well-recognized fact that impropertreatment can aggravate impaired glucose tolerance and insulinresistance, leading to frank diabetes. Thiazolidinediones of formula 1as well as the novel intermediates 14 & 13 of the present invention areuseful in the treatment of diabetes, and affect lipid metabolism.

Pioglitazone belongs to the thiazolidinedione group of antidiabetics.Later it has been found that its antidiabetic effect consists inreducing insulin resistance, thereby improving glucose homeostaseswithout increasing insulin secretion, unlike most other antidiabetics.For these extraordinary characteristics this product is of greatimportance for the treatment of non-insulin dependent diabetes mellitus.Combination with insulin or other antidiabetics can further increase itseffect.

Methods for production of various thiazolidinedione derivatives aredescribed in U.S. Pat. No. 4,687,777; Drugs of Future, 15,1080 (1990);Chemical and Pharmaceutical Bulletin, 30, 3563 (1982); 30, 3580 (1982)and 32, 2267 (1984). These methods invariably comprise low temperaturediazotisation, condensation with lachrymetric and readily polymerizablereagent acrylic ester in the presence of a copper catalyst by Meerweinarylation reaction to give a haloester, reacting it with thiourea togive an iminothiazolidine and finally hydrolyzing the same to get therequired thiazolidinedione derivative. These methods include multistepsynthetic processes and sometimes it is difficult to control Meerweinreaction at industrial scale, since it is an exothermic run-away type ofreaction accompanied by the generation of a large amount of nitrogengas, which is difficult to handle. Moreover, due to byproduct formation,purification becomes cumbersome. Besides, special measures are requiredin the Meerwein reaction for elimination of an extremely bad odour ofacrylic acid ester, which must be used in excess. The disposal of excessmaterial, along with heavy metals, requires additional effluenttreatment protocols. These issues make the known route disadvantageousboth technically and commercially.

Subsequently, new synthetic strategies have been reported in EP 0257781,which might lead to side product(s) eg, 2-vin-yl-5-ethyl pyridine fromtosylates, and require high pressure Raney Ni conversion of cyanide toformyl group. The purification of the intermediates is also difficult inthis process. In an yet another invention, microbial reductase has beenemployed to obtain pharmaceutically active thiazolidine derivatives (WO9310254).

Recently, Pioglitazone oxygenated metabolites have been patented (WO9322445) as potentially useful compounds for the treatment of diabetesand as insulin sensitizing agents (J. Med. Chem., 1996, 39, 5053). PCTPatent No. WO 93/13095 describes the use of cobalt ion, a ligand and areducing agent to convert the final step reduction of 5-methylenethiazolidinedione to saturated analogues.

U.S. Pat. No. 5,594,015 describes the new use of Pioglitazone for thetreatment of Psoriasis. Various other strategies to synthesizePioglitazone are disclosed in Patents EP 0506273. As discussed above inthe prior art, the known method to prepare compounds of general formula1, in particular, Pioglitazone, involves technically difficultprocedures to handle bad odour, low temperature diazotization, evolutionof large excess of gas and special precautions to handle effluents.

Besides, above mentioned procedures lead to the formation of unwantedimpurities, the removal of which is a time consuming process,Environmentally also, it requires evolution of HBr gas, which requiresupstream processing and consequent additional cost.

Subsequent to our provisional application a recent published article inOrganic Process Research Development, 2002, 6, 721-728 describes amethod for preparing compound of formula 14 when X═O

OBJECTIVE OF THE INVENTION

The present inventors have examined possibilities to find out processesto overcome the above drawbacks. The main objective of the presentinvention is to provide novel processes for the manufacture of variouspyridine substituted 5-[4-[2-(alkyl substitutedpyridyl)ethoxy]benzyl-2,4-thiazolidinedione derivatives, especiallyPioglitazone hydrochloride (1, R=5-ethyl). Another objective of thepresent invention is to report several new and novel intermediates forthe manufacture of Pioglitazone hydrochloride.

Above objectives as well as other objectives and advantages of thepresent invention will become apparent to those skilled in the art, aswe go through the following description, especially summary of theinvention.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a new, novel and generalprocess to prepare various pyridine substituted 5-[4-[2-(alkylsubstituted pyridyl)ethoxy]benzyl-2,4-thiazolidinedione derivatives ofgeneral formula 1, and their pharmaceutically acceptable salts. Thepresent invention especially provides a novel process to preparePioglitazone hydrochloride, via novel intermediates. This processinvolves lesser number of steps with high yield and uses key solidintermediates, which are operationally simple, and therefore offersopportunities for better commercial viability. Some of the novelintermediates described in this invention are 3, 5, 6, 9, 10b, 11, 13and 14.

Another objective of the present invention is to describe a process forpreparation of an intermediate 13 g, R=3-ethyl, X═H (Scheme II) forPioglitazone hydrochloride 1.

The most preferred objective of the present invention is to describe aprocess for the manufacture of Pioglitazone 1 (R=3-ethyl), and itspharmaceutically acceptable salts. The preferred method to prepare 1involves the synthetic sequence 2 to 9 to 13 to 14 to 1 and or 2 to 9 to13 to 1.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a novel process to prepare substituted5-[4-[2-(alkyl substituted pyridyl)ethoxy]benzyl-2,4-thiazolidinedionederivatives of general formula 1, and their pharmaceutically acceptablesalts Referring to the general formula 1, where R is denoted by straightchain or branched alkyl group of one to six carbon atoms, such asmethyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl,tert-butyl, pentyl, iso-pentyl, neo-pentyl, hexyl etc, more preferablythe lower alkyl groups of one to three carbon atoms. Such an alkyl groupmay be substituted in any position of the pyridine ring. The mostpreferred substituent and position for R in pyridine is 5-ethyl forPioglitazone 1.

The starting materials, 2-vinyl-5-ethyl pyridine (21 (R=5-ethyl,Scheme 1) and 5-ethyl-pyridine-2-carboxaldehyde (7), (R=5-ethyl),required for carrying out the multistep synthetic operations involvedwith this invention are known compounds, which may be easily preparedfrom commercially available 5-ethyl-2-pyridyl-2-ethanol or5-ethyl-2-methyl pyridine, by those skilled in the art, usingconventional methods.

The synthetic sequence comprises involvement of several novelintermediates eg. 9, 13, 14, 3, 6, 5, 10a and 10b with possibilities ofvaried substituents in 9, 13 and 14 (X O═OH, Cl, Br, OTs, OMs, SO₃H)(Scheme I, II & III). Many of these novel intermediates eg. 9, 13 and 14are inter convertible. For example, 9a (X═OH) which can be convertedinto 9b (X═Cl) or to 9d (X═OMs) or to 9e (X═OTs). The most preferredsynthetic strategy to prepare 1 involves the synthetic sequence 2 to 9to 13 to 14 to 1 (Scheme I/II) and/or 2 to 2 to 13 to 1.

The synthesis of novel key inter mediate 9 with various substitutionpatterns eg. 9a X═OH, 4-[2-hydroxy-2-[5-ethyl-pyridyl]ethoxybenzaldehyde; 9b X═Cl, 4-[2-chloro-2-[5-ethylpyridyl]ethoxybenzaldehyde; 9c X═Br, 4-[2-bromo-2-[5-ethylpyridyl]ethoxybenzaldehyde;9d X═OMs, 4-[2-mesyl-2-[5-ethylpyridyl]ethoxybenzaldehyde; 9e X═OTs,4-[2-p-tosyl-2-[5-ethylpyridyl]ethoxybenzaldehyde; 9f X═OSO₃H4-[2-hydroxy sulfonyloxy-2-[5-ethylpyridyl]ethoxybenzaldehyde etc, canbe achieved by reacting p-hydroxy benzaldehyde with suitable inorganicbase and suitable electrophiles eg. bromohydrin 3, epoxide 6, ordibromide 5, or cyclic sulfate 10a, or cyclic sulfite 10b in suitablesolvents. Suitable inorganic bases include but are not limited to sodiumcarbonate, potassium carbonate, cesium carbonate, sodium hydroxide,potassium hydroxide, sodium hydride, and the like. Suitable polar andneutral solvents for the above transformation include but are notlimited to dimethyl sulfoxide, dimethyl formamide, tetrahydrofuran,dimethoxyethane, acetonitrile, toluene, methanol, ethanol, tert-butanol,isopropyl alcohol and the like, in a ratio 3 to 50 volume with respectto the starting material. Occasionally, potassium salt ofp-hydroxybenzaldehyde (8) is used to couple with epoxide (6) or cyclicsulfite (10b), under above conditions to prepare 9a. Phase transfercatalysis e.g. PEG-2000, PEG-4000 and 18-C-6 may also be employed forbetter yield and quality. The usual impurities formed in these reactionsare isomeric primary hydroxyaldehyde (see Example 17) and2-acetyl-5-ethyl pyridine. Alternatively, 2 can be reacted to 8 in onestep to give 9c X═Br, via some of the synthetic transformationsdescribed in Larrock's book p 642. Preferably, use of N-bromosuccinimidewith 2 in the presence of 8, in an inert solvent can give 9c X═Br.Similarly, use of N-chloro-succinimide can lead to 9b, X═Cl in one step.

Several methods can be employed for formation of bromohydrin 3 fromvinyl pyridine 2. Suitable methods involve use of N-bromosuccinimide (1to 3 eq) in a suitable solvent in the presence of at least oneequivalent of water. Suitable solvents for bromohydrin 3 formation aredimethyl sulfoxide, acetone, tetrahydrofuran, tert-butanol,dimethoxyethane along with varied proportion of water in a ratio of 3 to50 volume. Treatment of base e.g. K₂CO₃, Na₂CO₃, NaOH, KOH withbromohydrin 3 can give the corresponding epoxide 6. The usual impuritiesformed in this reaction are isomeric bromohydrin and 2-acetyl-5-ethylpyridine Alternatively, one can also form epoxide 6 directly from olefin2 via oxidation. Preferably one can couple the bromohydrin formation(2→3) and epoxide formation (3→6) in one step, in an identical manner,as discussed above.

Bromination of olefin 2 with bromine in a neutral solvent e.g.dichloromethane, carbon tetrachloride, can give 5. Similarly, cyclicsulfate 10a may be prepared via oxidation of cyclic sulfite 10b, whichin turn may be obtained form diol 11 by reacting with thionyl chloride,in the presence of bases e.g. pyridine, triethylamine. The formation ofdiol 11, can be achieved from diacetate 17, by treatment with base inwater or methanol or ethanol. Alternatively, one can also prepare diol11, from the diacetate 17 which in turn can be obtained from N-oxide of5-ethyl-2-pyridyl-2-ethanol as shown in scheme I. In an the abovetransformations (Scheme I) upon completion of the reaction, the desiredcompound is easily isolated from the reaction mixture in a mostconventional manner eg. extracting in organic layer, washing with water,drying organic layer, concentrating and purifying/crystallizing thedesired final product.

As mentioned earlier, some of the substituents in 9, areinterconvertible. Thus, alcohol 9a X═OH, may be transformed to chloride9b X═Cl by reacting with thionyl chloride in an inert solvent e.g.toluene, dichloro methane, chloroform. Similarly, bromide 9c X═Br can beobtained by treating alcohol 9a X═OH with PBr₃. Tosylation (9e X═OTs) ofalcohol 9a X═OH, is achieved by reacting with TosCl (p-toluene sulfonylchloride) in the presence of an organic or inorganic base. Similarly,mesylated compound 9d X═OMs, may be prepared by reacting alcohol 9a X═OHwith mesyl chloride (methane sulfonyl chloride) in the presence of abase.

The condensation of variously substituted aromatic aldehyde 9a-e with5-20% excess molar ratio of 2,4-thiazolidinedione 12 is accomplished byazeotropic removal of water in a suitable solvent and in the presence ofan organic base and catalytic amount of organic acid. Suitable organicbases include, but are not limited to ammonia, methyl amine, ethylamine, n-butyl amine, pyrrolidine, piperidine, pyridine, morpholine,piperazine, diethylamine, di-isopropyl amine, triethyl amine and thelike; whereas suitable catalytic acids include, but are not limited toacetic acid, benzoic acid, p-toluene sulfonic acid hydrochloric acid,hydrobromic acid and the like. Suitable organic solvents for suchcondensation include, but are not limited to methanol, ethanol,propanol, 2-propanol, butanol, iso-butanol, 2-methoxyethanol, dimethylformamide, dimethyl sulfoxide, sulfolane, acetonitrile, dioxolane,dimethoxyethane, toluene, acetic acid and the like.

The chemoselective reduction of 13a-e (X═OH, Cl, Br, OMs, OTs) to 14a-e(X═OH, Cl, Sr, OMs, OTs) is accomplished by usual double bond reducingmethodologies described in R. C. Larrock, “Comprehensive OrganicTransformations”, John Wiley & Sons, Inc, 1999, 2^(nd) Ed, (hereinreferred to as Larrock's book) p 7-8. In particular, conversion of 13a(X═OH) to 14a (X═OH) is achieved by reducing with metal borohydrides ina suitable solvent, in the presence of a cobalt catalyst and a ligand.Suitable solvents, include but are not limited to methanol, ethanol,iso-propanol, acetone, dimethyl formamide (DMF) and tetrahydrofuran.Suitable cobalt catalyst include CoCl₂ (Cobaltous chloride), Co(OAC)₂(Cobaltous acetate) or CoCl₃ (Cobaltic chloride), Some of the ligandsuseful for this transformation are 2,2′-bipyridyl, 1,10-phenanthrolineand dimethyl glyoxime. Sodium borohydride is the preferred reducingagent, but other borohydrides such as lithium borohydride, potassiumborohydride, tetraalkylammonium borohydride or Zinc borohydride can alsobe used. The approximate molar ratio of sodium borohydride, dimethylglyoxime and cobaltous chloride with respect to the starting materialwas 3 to 4:0.4 to 0.6:0.05 to 0.2.

Alternatively, chemoselective reduction of 13 to 14 is accomplishedunder catalytic reduction conditions in a suitable solvent in thepresence of a suitable catalyst. Suitable solvents include but are notlimited to alkanols such as methanol, ethanol, propanol etc; ethers suchas dioxane, dimethoxyethane, tetrahydrofuran, and other miscellaneoussolvents eg. ethyl acetate, acetic acid, dimethyl formamide,N-methylpyrrolidine, either alone or in combinations thereof. Suitablecatalysts employed in this transformation include, but are not limitedto palladium black, palladium charcoal, palladium on barium sulfate,palladium on barium carbonate, platinum oxide, platinum on carbon, RaneyNickel and the like.

By varying experimental conditions in the above two reducing conditionseg. alkali metal borohydrides and catalytic hydrogenation conditions,the transformation from 13 to 14 and finally 14 to 1 may be accomplishedin one step, especially if the substituents in 13 are X═Cl, Br, OTs,OMs. Usually, 3 to 10 molecular equivalents of metal borohydridesmentioned above, and high reflux temperature are required to accomplishboth transformations in one step.

For deoxygenation of 13a or 14a (X═OH), to 1 (X═H), triethyl silaneinduced reduction in the presence of a suitable protic acids areadvantageous. Some of the protic acids used include, but are not limitedto conc. sulfuric acid, acetic acid, triflic acid, Nafion-H,trifluoroacetic acid and the like. Alternatively, deoxygenation withAlCl₃ in the presence of 10% Pd—C and cyclohexene as hydrogen donor isalso possible. There are several other useful methods described inLarrock's book p 44-45, to accomplish similar transformations and anyone of them may be advantageously used, so long as they achieve ourobjectives.

The transformation of 14b-e (X═Cl, Br, OMs, OTs) or its salts to 1 mayalso be achieved by reacting with zinc (molar ratio 0.5 to 2 w.r.t. 14)in acetic acid or propionic acid or HCl, under reflux conditions, orRaney nickel or 10% Pd—C in a suitable solvent like MeOH, EtOH,isopropanol, H₂O, THF and the like or their mixtures thereof, optionallyin presence of additives like NH₄Cl, TMEDA and the Like. The usualimpurities formed in the reaction are ether cleavage products e.g.5-ethyl-2-vinyl pyridine 2 and 15, Subsequently the suitable salt of 1preferably HCl salt can be prepared in methanol, ethanol, isopropanoland the like.

Alternatively, the useful intermediates 13a-f or 14a-2 may also beobtained by reacting the key intermediates 3, 5, 6, 10a and 10b withanother advanced intermediate unsaturated benzylidene type 15 orsaturated para-hydroxybenzyl substituted thiazolidinedione 15, known inprior art, in the presence of a base (Scheme III), similar to asdescribed above for nucleophilic attack of p-hydroxy benzaldehyde 8 tothe above key intermediates 3, 5, 6, 10a and 10b (Scheme I). Thereagents, solvents and reaction condition can be advantageouslyutilized, as described earlier for similar transformation.

The various novel intermediates 3, 5, 6, 9, 10b, 11, 13 and 14 describedin the present invention may be converted to corresponding salts byprocedures known in prior art. For example, with pyridine ring in theseintermediates, they can be converted to acid addition to salts withacids such as tartaric acid, mandelic acid, fumaric acid, malic acid,lactic acid, maleic acid, salicylic acid, citric acid, ascorbic acid,benzene sulfonic acid, p-toluene sulfonic acid, hydroxynaphthoic acid,methane sulfonic acid, acetic acid, benzoic acid, succinic acid,palmitic acid, hydrochloric acid, hydrobromic acid, sulfuric acid,nitric acid and the like in solvents such as water, alcohols, ethers,ethyl acetate, dioxane, THF, acetonitrile, DMF or a lower alkyl ketonesuch as acetone, or mixtures thereof. Many of these salts are solids andoffer operational simplicity for purification and manufacturing.Similarly, thiazolidinediones in 13 and 14 can be converted to theircorresponding cationic salts such as sodium ion, potassium ion, calciumion or an ammonium ion and the like.

The process described in the present invention is demonstrated in theexamples illustrated below. These examples are provided as illustrationand should not be considered as limiting the scope of invention in anyway. In all these examples R=5-ethyl, and X is indicated in the titlesof examples,

EXAMPLE 1 2-Bromo-1-(5-ethyl pyridin-2-yl)-ethanol (3)

To a stirred mixture of 225 mL 1,4-dioxane and 225 mL water, 75 g(0.5639 mol) of 5-ethyl-2-vinyl-pyridine was added, followed by 149 g(0.8371 mol) N-bromosuccinimide was added in to it, Reaction mixture wasstirred at 25-30° C. for 4 hr. and subsequently quenched with excesswater. Product was extracted with dichloromethane. Organic layer wasseparated and dried over calcium chloride. On concentrating the organiclayer and purifying the residue, it gave 110.24 g (85%) of desiredproduct.

The product obtained was characterized by IR, Mass, ¹³C NMR and ¹H NMR,which are as given below.

IR spectrum (cm⁻¹) 3200 (O—H str.), 1085 (C—O Str.), 715 (C—Br str.)Mass spectrum (m/z) 230.1 (M)⁺ ¹³C-NMR (DMSO-d₆) δ 153.38, 145.33,142.35, 140.40, 124.40, 68.29, 38.11, 24.60, 14.56 ¹H-NMR (DMSO-d₆) δ8.03-8.68 (3H, m), 5.37 (1H, t), 3.91 (2H, d), 2.76 (2H, q), 1.22 (3H,t)

EXAMPLE 2 2-Bromo-1-(5-ethyl pyridin-2-yl)-ethanol (3)

To a solution at −5° C., of 50 g (0.3759 mol) 5-ethyl-2-vinyl-pyridinedissolved in a mixture of 2504 mL dimethylsulfoxide and 13.5 my waterwas added 99.3 g (0.5578 mole) N-bromosuccinimide and stirring wascontinued for 30 min. at 0 to −5° C. Reaction mixture was quenched with2500 mL water and the product was extracted with dichloromethane.Organic layer was dried (calcium chloride); concentrated and purified toget the desired product. Yield of the product was 76.09 g (88%). The twoside products in this reaction found were 2-acetyl-5-ethyl-pyridine (5%)and 2-(1-bromo vinyl)-5-ethyl-pyridine (6%).

The product obtained was characterized by IR, Mass, ¹³C NMR and ¹H NMR,which was found to be identical with the product obtained in example 1.

EXAMPLE 3 2-Bromo-1-(5-ethyl pyridin-2-yl)-ethanol (3)

5.5 g (0.0344 mol) liq. Bromine was added to a solution of 7.83 g(0.0658 mol) KBr dissolved in 100 ml water. Reaction mixture was heatedto 60-65° C. and 5 g (0.0376 mol) of 5-ethyl-2-vinyl-pyridine was addedinto it in 10 min. Reaction mixture was stirred for 30 min. and quenchedwith excess of water. Product was extracted with dichloromethane, whichwas separated, dried, concentrated and purified to get 7.43 g (86%) ofthe titled product.

The product obtained was characterized by IR, Mass, ¹³C NMR and ¹H NMR,which was found to be identical with the product obtained in example 1.

EXAMPLE 4 2-Bromo-1-(5-ethyl pyridin-2-yl)-ethanol (3)

The procedure described in example 1 was repeated, except flattetrahydrofuran was used as solvent, and substantially the same resultswere achieved. In this particular case, the final product2-bromo-1-(5-ethyl pyridin-2-yl)-ethanol obtained was 106.35 g (82%), isto identical in every respect with the product of example 1.

EXAMPLE 5 2-Bromo-1-(5-ethyl pyridin-2-yl)-ethanol (3)

Into 75 mL 25% aqueous tertiary butanol 5 g (0.0372 mol)5-ethyl-2-vinyl-pyridine was added, followed by the addition of 8 g(0.0446 mole) N-bromosuccinimide in 10 min, Reaction mixture was stirredat 25 to 30° C. for 1 hr. and quenched with excess water. Product wasextracted with dichloromethane. Organic layer was dried (calciumchloride), concentrated and the residue obtained was purified to obtain8.21 g (95%) of the desired product. The impurity profile in thisreaction was similar to the impurity profile described in example 2.

The product obtained was characterized by IR, Mass, ¹³C NMR and ¹H NMR,which was found to be identical with the product obtained in example 1.

EXAMPLE 6 2-Bromo-1-(5-ethyl pyridin-2-yl)-ethanol (3)

The procedure described in example 5 was repeated except that 5% aqueoustertiary butanol was used as solvent, and substantially the same resultswere achieved. In this particular case, the final product2-bromo-1-(5-ethyl pyridin-2-yl)-ethanol obtained was 8.04 g (93%), isidentical in every respect with the product of example 1.

EXAMPLE 7 5-Ethyl-2-oxiranyl-pyridine (6)

To a stirred solution of 10 g (0.0426 mol) of 2-bromo-1-(5-ethylpyridin-2-yl)-ethanol dissolved in 50 mL of methanol, 6.86 g (0.0511mol) potassium carbonate was added at 25-30° C. and stirring wascontinued for 1 hr. Subsequently filtered and methanol was concentratedto furnish 5.8 g (90%) of the desired product.

The product obtained was characterized by IR, Mass, ¹³C NMR and ¹H NMRwhich are as given below.

IR spectrum (cm⁻¹) 2875, 2972 (saturated C—H str.), 987 (C—O—C str.)Mass spectrum (m/z) 150.1 (M + H)⁺ ¹³C-NMR (CDCl₃) δ 154.35, 149.04,138.80, 136.08, 119.0, 63.61, 50.16, 25.76, 15.23 ¹H-NMR (CDCl₃) δ7.14-8.41 (3H, m), 3.98 (1H, d), 2.94-3.16 (2H, m), 2.68 (2H, q), 1.26(3H, t)

EXAMPLE 8 5-Ethyl-2-oxiranyl-pyridine (6)

The procedure described in example 7 was repeated except that 25%aqueous tert-butanol was used as solvent, and substantially the sameresults were achieved. In this particular case, the final product5-ethyl-2-oxiranyl-pyridine obtained was 6.34 g (98%), is identical inevery respect with the product of example 7.

EXAMPLE 9 5-Ethyl-2-oxiranyl-pyridine (6)

The procedure described in example 7 was repeated except that isopropylalcohol was used as solvent, and substantially the same results wereachieved. In this particular case, the final product5-ethyl-2-oxiranyl-pyridine obtained was 5.89 g (91%), is identical inevery respect with the product example 7.

EXAMPLE 10 5-Ethyl-2-oxiranyl-pyridine (6)

The procedure described in example 7 was repeated, except thatdimethylsulfoxide was used as solvent, and substantially the sameresults were achieved. In this particular case, the final product5-ethyl-2-oxiranyl-pyridine obtained was 6.02 g (93%), is identical inevery respect with the product of example 7.

EXAMPLE 11 5-Ethyl-2-oxiranyl-pyridine (6)

The procedure described in example 7 was repeated, except that 2%aqueous dimethylsulfoxide was used as solvent, and substantially thesame results were achieved. In this particular case, the final product5-ethyl-2-oxiranyl-pyridine obtained was 6.02 g (93%), is identical inevery respect with the product of example 7.

EXAMPLE 12 5-Ethyl-2-oxiranyl-pyridine (6)

The procedure described in example 7 was repeated, except that toluenewas used as solvent, and substantially the same results were achieved.In this particular case, the final product 5-ethyl-2-oxiranyl-pyridineobtained was 5.96 g (92%), is identical in every respect with theproduct of example 7.

EXAMPLE 13 5-Ethyl-2-oxiranyl-pyridine (6)

The procedure described in example 7 was repeated, except that 1.02 g(0.0426 mol) sodium hydride was used as base, and substantially the sameresults were achieved. In this particular case, the final product5-ethyl-2-oxiranyl-pyridine obtained was 6.02 g (93%), is identical inevery respect with the product of example 7.

EXAMPLE 14 5-Ethyl-2-oxiranyl-pyridine (6)

The procedure described in example 7 was repeated, except that 1.7 g(0.0426 mol) sodium hydroxide was used as base, and substantially thesame results were achieved. In this particular ease, the final product5-ethyl-2-oxiranyl-pyridine obtained was 5.83 g (90%), is identical iiievery respect with the product of example 7.

EXAMPLE 15 5-Ethyl-2-oxiranyl-pyridine (6)

To a mixture of 750 mL tert-butanol and 2250 mL water, 200 g (1.488 mol)of 5-ethyl-2-vinyl-pyridine was dissolved and under stirring 324 g(1.786 mol) N-bromosuccinimide was added in 30 min. at 25-30° C.Stirring was continued for 1 hr. and 178.6 g (4.46 mol) of NaOHdissolved in 2250 mL water was added into it. Reaction mixture wasstirred for 45 min. Product was extracted twice with 1100 mL methyltert-butyl ether. Organic layers were combined, washed with brine, driedover magnesium sulfate and concentrated in vacuo to yield 206.13 g (92%)of 6.

The product obtained was characterized by IR, Mass, ¹³C and ¹H NMR isidentical in every respect with the product of example 7.

EXAMPLE 16 5-Ethyl-2-oxiranyl-pyridine (6)

To a stirred solution of 400 g (2.974 mol) 5-ethyl-2-vinyl-pyridinedissolved in a mixture of 1000 mL of dimethyl sulfoxide and 106 mLwater, was added 741.9 g (4.16 mol) N-bromosuccinimide at 0 to −5° C.Reaction mixture was stirred for 1 hr. The progress of reaction wasmonitored by TLC and after complete consumption of5-ethyl-2-vinyl-pyridine, 833 g (6.015 mol) of K₂CO₃ along with 400 mLmethanol was added at 25-30° C. Stirring was continued for 1 hr. andafter subsequent work-up 358.49 g (80%) of the desired product wasobtained.

The product obtained was characterized by IR, Mass, ¹³C NMR and ¹H NMR,which was found to be identical with the product obtained in example 7.

EXAMPLE 17 4-[2-(5-Ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde(9a)

11.35 g (0.283 mol) of sodium hydride in 10 mL dimethylformamide wasadded into a solution of 19.27 g (0.158 mol) of 4-hydroxy benzaldehydedissolved in 100 mL dimethylformamide and stirred for 5 min. To this wasadded 30 g (0.129 mol) of 2-bromo-1-(5-ethyl-pyridin-2-yl)-ethanoldissolved in 1000 mL dimethylformamide slowly and stirring was continuedfor 1 hr. at 25 to 30° C. Reaction mixture was heated at 80 to 90° C.for 14 hr, cooled to 25° C. and poured in excess of water. Product wasextracted with diethyl ether. Diethyl ether layer was dried (magnesiumsulfate) and concentrated to obtain 30.04 g (85%) of crude product.

The crude product was suspended in 140 mL diisopropyl ether and refluxedat 70° C. with charcoal. After filtration and cooling 24.03 g (68%)purified 4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde wasseparated and 5.1 g (14.4%) of its regioisomer was also obtained.

The product obtained was characterized by IR, Mass, ¹³C NMR and ¹H NMRwhich are as given below.

IR spectrum (cm⁻¹) 1701 (C═O str.), 3413 (O—H str.) Mass spectrum (m/z)272.2 (M + H)⁺ ¹³C-NMR (CDCl₃) δ 190.75, 163.52, 155.53, 148.02, 138.70,136.26, 131.84, 129.96, 120.73, 114.79, 72.48, 71.15, 25.65, 15.19¹H-NMR (CDCl₃) δ 9.85 (1H, s), 6.98-8.41 (7H, m), 5.14 (1H, t), 4.5 (1H,brs), 4.28 (2H, d), 2.67 (2H, q), 1.25 (3H, t) Melting point 80-83° C.

The regioisomer4-[1-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde of the titledproduct separated was a low melting solid and was characterized by IRMass, ¹³C NMR and ¹H NMR, which are as given below.

IR spectrum (cm⁻¹) 1683 (C═O str.), 3475 (O—H str.) Mass spectrum (m/z)272.1 (M + H)⁺ ¹³C-NMR (CDCl₃) δ 191.1, 162.9, 154.7, 148.7, 138.3,136.1, 131.7, 129.6, 120.9, 114.6, 72.1, 65.6, 24.9, 15.1 ¹H-NMR (CDCl₃)δ 9.79 (1H, s), 7.05-8.43 (7H, m), 5.45 (1H, t), 3.84 (2H, d), 2.67 (2H,q), 1.20 (3H, t)

EXAMPLE 18 4-[2-(5-Ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde(2)

Into a solution of 2.9 g (0.0234 mol) of 4-hydroxy benzaldehydedissolved in 100 mL dimethylformamide, 8.94 g (0.063 mol) of potassiumcarbonate in 20 mL dimethylformamide was added in 10 min, followed byslow addition of 5 g (0.0213 mol) of2-bromo-1-(5-ethyl-pyridin-2-yl)-ethanol dissolved in 1000 mLdimethylformamide. Reaction mixture was stirred for 1 hr. at 25 to 30°C., heated at 80 to 90° C. for 14 hr. and poured into excess of water at25° C. Product was extracted with diethyl ether. Subsequentconcentration in vacuo of the organic layer and purification asdescribed earlier yielded 3.97 g (67.5%) of the desired product, m.p.80° C.

The product obtained was characterized by IR, Mass, ¹³C NMR and ¹H NMR,which was found to be identical with the product obtained in example 17.

EXAMPLE, 19 4-[2-(5-Ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde(9a)

Into a solution of 22.6 g (0.181 mol) of 4-hydroxy benzaldehydedissolved in 75 mL tertiary butanol, was added 38.5 g (0.278 mol) ofpotassium carbonate in 10 min. Reaction mixture was refluxed for 1 hr.and 15 g (0.06 mol) of 2-bromo-1-(5-ethyl-pyridin-2-yl)-ethanoldissolved in 75 mL tertiary butanol was added slowly in one hr. Reactionmixture was refluxed further for 10 hr. and at 25° C. poured into excessof water. Product was extracted with toluene. Subsequent concentrationunder reduced pressure and purification gave the desired product. Yieldof the product was 12.37 g (70%). m.p. 80° C.

The product obtained was characterized by IR Mass, ¹³C N and ¹H NMR,which was found to be identical with the product obtained in example 17.

EXAMPLE 20 4-[2-(5-Ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde(9a)

The procedure described in example 19 was repeated except that isopropylalcohol was used as solvent, and substantially the same results wereachieved. In this particular case, the final4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde obtained was11.49 g (65%) is identical in every respect with the product of example17. m.p. 81° C.

EXAMPLE 21 4-[2-(5-Ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde(9a)

The procedure described in example 19 was repeated except that methanolwas used as solvent, and substantially the same results were achieved.In this particular case, the final4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde obtained was11.31 g (64%), is identical in every respect with the product of example17. m.p. 82° C.

EXAMPLE 22 4-[2-(5-Ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde(9a)

The procedure described in example 19 was repeated except thatdimethylsulfoxide was used as solvent, and substantially the sameresults were achieved. In this particular case, the final4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde obtained was12 g (68%) is identical in every respect with the product of example17m.p. 83° C.

EXAMPLE 23 4-[2-(5-Ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde(9a)

The procedure described in example 19 was repeated except that toluenewas used as solvent, and substantially the same results were achieved.In this particular case, the final4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde obtained was10.6 g (60%), is identical in every respect with the product of example17. m.p. 80° C.

EXAMPLE 24 4-[2-(5-Ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde(9a)

Into a solution of 9.635 kg (72.99 mol) of 4-hydroxy benzaldehydedissolved in 50 lit. dimethylformamide was added 5.675 kg (236.45 mol)of sodium hydride in 5 lit. dimethylformamide and stirred for 15 min. Tothis was added 15 Kg (65.22 mol) of 2-bromo-1-(5-ethylpyridin-2-yl)-ethanol dissolved in 500 lit dimethylformamide andstirring was continued for 1 hr. at 25 to 30° C. Reaction mixture washeated at 80 to 90° C. for 14 hr., allowed to cool to 25° C. and excessof water was added into it. Product was extracted with diethyl ether.Organic layer was dried (magnesium sulfate) and concentrated to obtaincrude product, which was purified in methyl tert-butyl ether asdescribed in example 17 to obtain 12,195 Kg (69%) pure4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde. m.p. 83° C.

The impurity profile in this reaction was similar to the impurityprofile of example 17.

EXAMPLE 25 4-[2-(5-Ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde(9a)

To a flask fitted with an overhead stirrer, a thermometer and acondenser was added 500 g (3.759 mol) 5-ethyl-2-vinyl-pyridine dissolvedin 7500 mL of 25% aqueous tertiary butanol. To this was added 802 g (4.5mol) N-bromosuccinimide at 25-30° C. in 30 min. Reaction mixture wasstirred for 2 hr. The progress of reaction was monitored by TLC andafter complete consumption of the 5-ethyl-2-vinyl-pyridine, 762 g (5.52mol) of K₂CO₃ was added in one lot along with 537 g (4.4 mol) 4-hydroxybenzaldehyde. Reaction mixture was stirred for 18 hr. at 75-80° C.Subsequent work-up in water, extraction with ethyl acetate andpurification yielded 805 g (79%) of the titled product m.p. 83° C.

The product obtained was characterized by IR, Mass, ¹³C NMR and ¹H NMR,which was found to be identical with the product obtained in example 17.The impurity profile in this reaction was similar to the impurityprofile of example 17.

EXAMPLE 26 4-[2-(5-Ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde(9a)

To a flask fitted with an overhead stirrer, a thermometer and acondenser was added a solution of 12 Kg (90.22 mole)5-ethyl-2-vinyl-pyridine dissolved in a mixture of 45 lit. tert-butanoland 135 lit. water at 25° C., followed by addition of 19.26 Kg (108.25mole) N-bromosuccinimide and reaction mixture was stirred for 1.5 hr.135 lit. aqueous 2N NaOH solution was added to the reaction mixture andstirring was continued for further 45 min. Progress of reaction wasmonitored by TLC and after completion of reaction, product was extractedwith 120 lit. methylene chloride, Layers were separated organic layerwas washed with 72 lit. brine solution, dried (magnesium sulfate) andconcentrated under reduced pressure. The residual mass obtained wasadded into a stirred mixture of 15.96 Kg (130.8 mole) 4-hydroxybenzaldehyde dissolved in 130 lit. toluene and 5.23 Kg (1307 mole) NaOHdissolved in 120 lit. water. To this was added 2.21 Kg PEG 4000 andstirred for 17 hr. at 78° C. Subsequent work-up gave 20.538 Kg (84%)4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde, m.p. 82° C.

The product obtained was characterized by IR, Mass, ¹³C NMR and ¹H NMR,which was found to be identical with the product obtained in example 17.The impurity profile in this reaction was similar to the impurityprofile of example 17.

EXAMPLE 27 4-[2-(5-Ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde(9a)

Into a stirred mixture of 4.5 lit. tert-butanol and 13.5 lit, water wasadded 1.2 Kg (9.02 mole) 5-ethyl-2-vinyl-pyridine at 25° C. To this wasadded 1.926 Kg (10.82 mol) N-bromosuccinimide and reaction mixture wasstirred for 11. hr. 13.5 lit. aqueous 2N NaOH solution was added to thereaction mixture and stirring was continued for further 45 min. Progressof reaction was monitored by TLC and after completion of reaction,product was extracted with 12 lit. methyl tert-butyl ether. Layers wereseparated, organic layer was washed with 7.2 lit. brine solution, dried(magnesium sulfate) and concentrated under reduced pressure. Theresidual solid obtained was added into a stirred mixture of 1.59 Kg (13mol) 4-hydroxy benzaldehyde dissolved in 13 lit. toluene and 523 g (130mol) NaOH dissolved in 120 lit. water. To this was added 221 g PEG 2000and stirred for 17 hr. at 78° C. Subsequent work-up gave 2.029 Kg (83%)4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde. m.p. 81° C.

The product obtained was characterized by IR, Mass, ¹³C NMR and ¹H NMRwhich was found to be identical with the product obtained in example 17.The impurity profile in this reaction was similar to the impurityprofile of example 17.

EXAMPLE 28 4-[2-(5-Ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde(9a)

To a solution of 5 g (0.03759 mol) 5-ethyl-2-vinyl-pyridine dissolved in75 mL of 25% aqueous tertiary butanol added 8.02 g (0.045 mol)N-bromosuccimide at 25-30° C. in 30 min. Reaction mixture was stirredfor 2 hr. The progress of reaction was monitored by TLC and aftercomplete consumption of the 5-ethyl-2-vinyl-pyridine, 6.01 g (0.03759mol) potassium salt of 4-hydroxy benzaldehyde was added, Reactionmixture was stirred for 18 hr. at 75-80° C. Subsequent work-up in waterand extraction with ethyl acetate yielded 8.04 g (79%) of the titledproduct, m.p. 81° C.

The product obtained was characterized by IR, Mass, ¹³C and ¹H NMR,which was found to be identical with the product obtained in example 17.

EXAMPLE 29 4-[2-(5-Ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde(9a)

To a mixture of 690 mL tert-butanol and 2075 mL water, 184.46 g (1.3869mol) of 5-ethyl-2-vinyl-pyridine was dissolved and under stirring 298.83g (1.6788 mol) N-bromosuccinimide was added in 30 min. at 25-30° C.Stirring was continued for 1 hr. and 164.7 g (4.117 mol) of NaOHdissolved in 2075 mL water was added into it. Reaction mixture wasstirred for 45 min, and extracted twice with 1000 mL methyl tert-butylether. Organic layers were combined, washed with brine, dried overmagnesium sulfate and concentrated in vacuo to yield 190 g residualmass. The concentrated product obtained was added to a stirred mixtureof 76 g (1.817 mol) NaOH dissolved in 1800 mL water and 223 g (1.817mol) 4-hydroxy benzaldehyde dissolved in 1900 mL toluene. To this wasadded 16.65 g (0.063 mol) 18 Crown-6 and stirred for 24 hr. at 78° C.Subsequent work-up yielded 304.44 g (81%)4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde. m.p. 83° C.

The product obtained was characterized by IR, Mass, ¹³C NMR and ¹H NMRwhich was found to be identical with the product obtained in example 17.The impurity profile in this reaction was similar to the impurityprofile of example 17.

EXAMPLE 305-{4-[2-(5-Ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzylidene}-2,4-thiazolidenedione (13, X═OH)

Into 50 mL methanol, 10 g (0.0369 mol)4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ehoxy]-benzaldehyde, 4.33 g(0.0369 mol) thiazolidin-2,4-dione, 0.43 mL (0.0099 mol) acetic acid,and 0.726 mL (0.0099 mol) piperidine were dissolved. Reaction mixturewas refluxed for 4 hr and cooling gave 12 g (88%) of the desiredproduct.

The product obtained was characterized by IR, Mass, ¹³C NMR, and ¹H NMR,which are as given below.

IR spectrum (cm⁻¹) 3500 (O—H str.), 1701, 1735 (C═O str.), 1037 (C—O—Cstr.) Mass spectrum (m/z) 371 (M + H)⁺ ¹³C-NMR (DMSO-d₆) δ 167.98,167.49, 160.38, 158.36, 148.0, 137.65, 135.90, 132.07, 131.79, 125.49,120.61, 120.29, 115.47, 72.47, 71.82, 25.02, 15.40 ¹H-NMR (DMSO-d₆) δ12.5 (1H, s), 7.01-8.32 (7H, m), 7.63 (1H, s), 5.80 (1H, s), 4.93 (1H,s), 4.1 (1H, dd), 4.3 (1H, dd), 2.64 (2H, q), 1.20 (3H, t) Melting point158-160° C.

EXAMPLE 315-{4-[2-(5-Ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzylidene}-2,4-thiazolidenediode (13, X═OH)

To a stirred solution of 20 g (0.0738 mol) of4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde, 8.66 g(0.0738 mol) thiazolidin-2,4-dione in 80 mL toluene, 0.86 (0.0198 mol)mL acetic acid and 1.45 mL (0.0198 mol) piperidine were added. Reactionmixture was refluxed for 2 hr. at 110° C. Water was removedazeotropically. The crude product was purified by addition of isopropylalcohol to yield 22.11 g (81%) yellow powdered desired product. m.p.160° C.

The product obtained was characterized by IR, Mass, ¹³C NMR, and ¹H NMR,which was found to be identical with the product obtained in example 30.

EXAMPLE 325-{4-[2-(5-Ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzylidene}-2,4-thiazolidenedione (13, X═OH)

0.29 mL (0.005 mol) acetic acid and 0.49 mL (0.005 mol) piperidine wereadded into a mixture of 13.58 g (0.05 mol)4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde and 5.9 g(0.05 mol) thiazolidin-2,4-dione, dissolved in 52 mL toluene. Reactionmixture was refluxed for 2 hr. at 110° C. Water was removedazeotropically. After removal of the water, sticky mass separated outfrom reaction mixture. 35 mL of isopropyl alcohol was added to reactionmixture at 60-70° C. and it was cooled to 25° C. Precipitated productwas filtered off and dried to obtain 15.57 g (84%) of the titledproduct. m.p. 158° C.

The product obtained was characterized by IR Mass, ¹³C NMR and ¹H NMR,which was found to be identical with the product obtained in example 30.

EXAMPLE 335-{4-[2-(5-Ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzylidene}-2,4-thiazolidenedione (13, X═OH)

The procedure described in example 30 was repeated except that 1.2 g(0.0099 mol) benzoic acid was used instead of acetic acid, andsubstantially the same results were achieved. In this particular case,the crude final product5-{4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzylidene}-2,4-thiazolidenedione obtained was purified as described earlier to get 11 g (81%) pureproduct, which is identical in every respect with the product of example30. m.p. 159° C.

EXAMPLE 345-{4-[2-(5-Ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzylidene}-2,4-thiazolidenedione (13, X═OH)

Into 132 mL methanol, 10 g (0.0369 mol)4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde, 4.74 g(0.0409 mol) thiazolidin-2,4-dione, 3.01 mL (0.0369 mol) pyrrolidinewere added. Reaction mixture was warmed at 40-45° C. for 1 hr. and 3 mL(0.0525 mol) acetic acid was added. After completion of reaction on TLC,methanol was concentrated under reduced pressure and desired product wasobtained as yellow powdered product. Yield of the product was 12.28 g(90%). m.p. 160° C.

The product obtained was characterized by IR, Mass, ¹³C NMR, and ¹H NMR,which was found to be identical with the product obtained in example 30.

EXAMPLE 355-{4-[2-(5-Ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzylidene}-2,4-thiazolidenedione (3, X═OH)

94.98 g (0.811 mol) Thiazolidin-2,4-dione was added in 800 mL methanolfollowed by the addition of 200 g (0.738 mol)4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde and 60.92 mL(0.738 mol) pyrrolidine. Reaction mixture was warmed at 50-55° C. for 2hr. and 48.26 mL (0.811 mol) acetic acid was added. Reaction mixture wasstirred at 30° C. for 1 hr. Product precipitated was filtered off andpurified using methanol to obtain yellow powdered desired product. Yieldof the product was 248.48 g (91%). m.p. 160° C.

The product obtained was characterized by IR, Mass, ¹³C NMR, and ¹H NMR,which was found to be identical with the product obtained in example 30.

EXAMPLE 365-{4-[2-(5-Ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzylidene}-2,4-thiazolidenedione (13, X═OH)

Into 40 lit. methanol, 4.749 Kg (40.55 mol) thiazolidin-2,4-dione, 10 Kg(36.9 mol) 4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehydeand 30.46 lit, (36.9 mol) pyrrolidine were added, Reaction mixture waswarmed at 50-55° C. for 2 hr. and was added 24.13 lit. (40.55 mol)acetic acid. Reaction mixture was stirred at 30° C. for 1 hr. Productprecipitated was filtered off and purified using methanol to obtain12.424 Kg (91%) of the desired product. m.p. 160° C.

The product obtained was characterized by IR Mass, ¹³C NMR, and ¹H NMR,which was found to be identical with the product obtained in example 30.

EXAMPLE 375-{4-[2-(5-Ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzyl}-2,4-thiazolidenedione (14, X═OH)

To a stirred mixture of 49 mL water and 84 mL dimethyl formamide (DMF),7 g (0.01891 mol)5-{4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzylidene}-2,4-thiazolidenedione, 1.91 (0.0164 mol) g dimethyl glyoxinme (DMG) and 0.21 (0.0009mol) g cobaltus chloride hexahydrate (CoCO₂.6H₂O) dissolved in 14 mL DMFwere added at 60-65° C. To that 3.9 g sodium borohydride in 21 mL waterwas added slowly. Reaction mixture was stirred at 60-65° C. for 3 hrs.Reaction mixture was poured into excess of water and was extracted withethyl acetate. Upon concentrating ethyl acetate, white product obtained.Yield of the product was 6.47 g (92%).

The product obtained was characterized by IR; Mass, ¹³C NMR, and ¹H NMR,which are as given below.

IR spectrum (cm⁻¹) 3523 (O—H str.), 1703, 1739 (C═O str.), 1037 (C—O—Cstr.) Mass spectrum (m/z) 373 (M + H)⁺ ¹³C-NMR (DMSO-d₆) δ 176.0, 171.0,158.39, 158.69, 147.9, 137.55, 135.8, 130.30, 128.68, 120.5, 115.38,72.24, 71.97, 51.0, 35.1, 25.02, 15.39 ¹H-NMR (DMSO-d₆) δ 11.96 (1H, s),6.84-8.37 (7H, m), 5.74 (1H, s), 4.91 (1H, dd), 4.82 (1H, dd), 4.0 (1H,dd), 4.2 (1H, dd), 3.25 (1H, dd), 3.04 (1H, dd), 2.55 (2H, q), 1.19 (3H,t) Melting point 119-121° C.

The final product was dissolved into substantial amount of isopropylalcohol and HCl gas was bubbled into it to get its correspondinghydrochloride salt which was characterized by IR Mass, ¹³C NMR and ¹HNMR, which are as given below.

IR spectrum (cm⁻¹) 3246 (O—H str.), 1685, 1743 (C═O str.), 1056 (C—O—Cstr.) Mass spectrum (m/z) 373.1 (M + H)⁺ ¹³C-NMR (CD₃OD) δ 175.66,171.63, 157.13, 153.8, 145.03, 142.03, 140.2, 130.37, 114.5, 70.82,68.1, 52.93, 36.2, 24.65, 14.61 ¹H-NMR (CD₃OD) δ 6.83-8.65 (7H, m), 5.45(1H, t), 4.65 (1H, dd), 4.33 (2H, m), 3.30 (1H, dd), 3.05 (1H, dd), 2.86(2H, q), 1.33 (3H, t) Melting point 146-148° C.

EXAMPLE 385-{4-[2-(5-Ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzyl}-2,4-thiazolidenedione (14, X═OH)

30 g (0.0794 mol)5-{4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzylidene}-2,4-thiazolidenedione was dissolved in 210 mL water. To this was added a mixture of 6.42(0.0553 mol) g DMG and 2.62 g (0.011 mol) CoCl₂.6H₂O dissolved in 60 mLDMF at 65-70° C., followed by slow addition of 12.33 (0.3332 mol) gsodium borohydride dissolved in 90 mL cold water at 70-85° C. Aftercomplete addition of sodium borohydride, reaction mixture was stirred at65-70° C. for 4 hr. To reaction mixture excess water was added andproduct was extracted with chloroform. Organic layer was separated,dried (calcium chloride) and concentrated under reduced pressure toafford 28.35 g (94%) white product. m.p. 119° C.

The product obtained was characterized by IR Mass, ¹³C NMR, and ¹NMRwhich was found to be identical with the product obtained in example 37.

EXAMPLE 395-{4-[2-(5-Ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzyl}-2,4-thiazolidenedione (14, X═OH)

Into 115 mL of water, 10 g (0.0256 mol),5-{4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzylidene}-2,4-thiazolidenedione, 0.62 g (0.0053 mol) DMG and 0.038 g (0.0001 mol) CoCl₂.6H₂Odissolved in 20 mL DMF were added at 65-70° C. To this 4.56 g (0.1232mol) sodium borohydride in 35 mL cold water was added slowly at 70-75°C. After complete addition of sodium borohydride, reaction mixture wasstirred at 65-70° C. for 4 hr, and poured into excess of water. Productwas extracted with chloroform. Layers were separated, organic layer wasdried and concentrated under reduced pressure to obtain white product.The product was recrystallized by a mixture of 0.5 v/wt ethanol and 15v/wt diisopropyl ether. Yield of the product was 9.45 g (94%). m.p. 119°C.

The product obtained was characterized by IR, Mass, ¹³C NMR, and ¹H NMR,which was found to be identical with the product obtained in example 37.

EXAMPLE 405-{4-[2-(5-Ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzyl}-2,4-thiazolidenedione (14, X═OH)

To a flask fitted with an overhead stirrer, a thermometer and acondenser was added a solution of 100 g (0.256 mol)5-{4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzylidene}-2,4-thiazolidenedione dissolved in 700 mL water at 65-70° C. To this was added 15.59 g(0.1344 mol) DMG and 6.42 g (0.0269 mol) CoCl₂.6H₂O dissolved in 200 mLDMF followed by slow addition of 30.67 g (0.8289 mol) sodium borohydridein 300 mL chilled water at 70-85° C. After complete addition of sodiumborohydride, reaction mixture was stirred at 65-70° C. for 4 hr. andpoured into excess of water. Subsequent work-up by extraction withmethyl tert-butyl ether and concentrating organic solvent under reducedpressure afforded 95.51 g (95%) white product. m p. 121° C.

The product obtained was characterized by IR, Mass, ¹³C NMR, and ¹H NMRwhich was found to be identical with the product obtained in example 37.

EXAMPLE 415-{4-[2-(5-Ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzyl}-2,4-thiazolidenedione (14, X═OR)

To a solution of 10 Kg (25.6 mol)5-{4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzylidene}-2,4-thiazolidenedione dissolved in 70 lit. water at 65-70° C. was added 1.559 Kg (13.44mol) DMG and 0.642 Kg (2.69 mol) CoCl₂.6H₂O dissolved in 20 lit. DMFfollowed by slow addition of 3.067 Kg (82.89 mol) sodium borohydride in30 lit. water at 70-85° C. After complete addition of sodiumborohydride, reaction mixture was stirred at 65-70° C. for 4 hr. andexcess of water was added to the reaction mixture. Subsequent work-upwith chloroform and concentrating organic solvent under reduced pressureafforded 9.551 Kg (95%) white product. m p. 120° C.

The product obtained was characterized by IR, Mass, ¹³C NMR, and ¹H NMR,which was found to be identical with the product obtained in example 37.

EXAMPLE 425-{4-[2-Chloro-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidenedione and HCl salt (14, X═Cl)

To 2 g (0.0053 mol) of5-{4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzyl}-2,4-thiazolidenedione dissolved in chloroform was added 1.34 g (0.0064 mol) PCl₅ at25-30° C. and reaction mixture was stirred for 3 hr. at 25-30° C.Reaction mixture was poured in excess of water and made basic with 10%Na₂CO₃ solution. Product was extracted with chloroform and on removingsolvent, 1.26 g (60%) of the desired product was obtained.

The product obtained was characterized by IR, Mass, ¹³C NMR, and ¹H NMR,which are as given below.

IR spectrum (cm⁻¹) 3400 (N—H str.), 1683, 1747 (C═O str.), 1051 (C—O—Cstr.) Mass spectrum (m/z) 391.2 (M + H)⁺ ¹³C-NMR (DMSO-d₆) δ 175.7,171.7, 156.7, 150.9, 145.0, 141.7, 141.5, 130.5, 129.5, 124.5, 114.6,69.5, 96.8, 52.9, 36.2, 24.9, 14.8 ¹H-NMR (DMSO-d₆) δ 12.0 (1H, s),6.88-8.65 (7H, m), 5.74 (1H, t), 4.86 (1H, dd), 4.66 (2H, m), 3.30 (1H,dd), 3.05 (1H, dd), 2.71 (2H, q), 1.17 (3H, t)

The final product was dissolved into substantial amount of tert-butylether and HCl gas was bubbled into it to yield its correspondinghydrochloride salt which characterized by IR, Mass, ¹³C NMR and ¹H Nwhich are as given below.

IR spectrum (cm⁻¹) 3369 (N—H str.), 1697, 1747 (C═O str.), 1055 (C—O—Cstr.), 715 (C—O—C str.) Mass spectrum (m/z) 391.2 (M + H)⁺ ¹³C-NMR(DMSO-d₆) δ 175.7, 171.7, 156.7, 150.3, 142.6, 129.5, 144.2, 142.2,124.9, 130.5, 114.7, 69.4, 56.2, 52.9, 39.4, 36.2, 24.9, 14.7 ¹H-NMR(DMSO-d₆) δ 13.12 (1H, br s), 12.0 (1H, s) 6.91-8.7 (7H, m), 5.82 (1H,t), 4.86 (1H, dd), 4.65 (2H, m), 3.0 (2H, m), 2.7 (2H, q), 1.19 (3H, t)Melting point 175-178° C.

EXAMPLE 435-{4-[2-Chloro-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidenedione (14, X═Cl)

A mixture of 1 g (0.0026 mol) of5-{4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzyl}-2,4-thiazolidenedione and 1.072 g (0.01 mol) CaCO₃ was added in 10 mL chloroform andcooled to 0° C. To this was added 0.671 (0.0032 mol) g PCl₅ in 3 min.Reaction mixture was stirred for 3 hr. After subsequent work-up inalkaline water, extracting product with chloroform and on concentrating0.6 g (58%) of the desired dark liquid was obtained.

The product obtained was characterized by IR, Mass, ¹³C NMR, and ¹H NMR,which was found to be identical with the product obtained in example 42.

EXAMPLE 445-{4-[2-Chloro-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidenedione (14, X═Cl)

The procedure described in example 42 was repeated on 10 g scale exceptthat dichloromethane was used as solvent, and substantially the sameresults were achieved. In this particular case, the final5-{4-[2-chloro-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidenedione obtained was 5.98 g (57%), is identical in every respect with theproduct of example 42.

EXAMPLE 455-{4-[2-Chloro-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidenedione (14, X═Cl)

15 g (0.0403 mol) of5-{4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzyl}-2,4-thiazolidenedione was suspended in 75 mL toluene. To this was added 12.56 g (0.0483mol) PCl₅ at 60° C. in 15 min. Heating was continued for 3 hr. Reactionmixture was poured in excess of water and made alkaline with 10% Na₂CO)₃solution. The product was extracted with chloroform and on concentratingdried organic layer in vacuo furnished 8.97 g (57%) of the titledproduct.

The product obtained was characterized by IR, Mass, ¹³C NMR, and ¹H NMR,which was found to be identical with the product obtained in example 42.

EXAMPLE 465-{4-[2-Chloro-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidenedione hydrochloride (14, X═Cl)

To a solution of 2 g (0.00537 mol) of5-{4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzyl}-2,4-thiazolidenedione dissolved in 30 ml dichloromethane was added 1.06 g (0.0134 mol)pyridine and cooled to −15° C. To this was added 1.2 g (0.0059 mol) PCl₅in 10 min, at −15 to −20° C. The reaction mixture was stirred for 2 hr.at −15 to −20° C., 1 hr. at −5 to 0° C., and 2 hr. at 20 to 25° C.Subsequent work-up and salt formation as described earlier yielded 1.17g (56%) of the desired product.

The product obtained was characterized by IR, Mass, ¹³C NMR, aid ¹H NMR,which was found to be identical with the product obtained in example 42.

EXAMPLE 475-{4-[2-Chloro-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidenedione hydrochloride (14, X═Cl)

The procedure described in example 46 was repeated on same scale exceptthat PCl₅ was taken 1.45 g (0.00697 mol) used, and substantially thesame results were achieved. In this particular case, the final5-{-4-[2-chloro-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidenedione hydrochloride obtained was 1.15 g (55%), is identical in everyrespect with the product of example 42.

EXAMPLE 485-{4-[2-Chloro-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidenedione hydrochloride (14, X═Cl)

The procedure described in example 46 was repeated on same scale exceptthat PCl₅ was taken 1.12 g (0.00537 mol) used, and substantially thesame results were achieved. In this particular case, the final5-{4-[2-chloro-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidenedione hydrochloride obtained was 1.19 g (57%), is identical in everyrespect with the product of example 42.

EXAMPLE 495-{4-[2-Chloro-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidenedione (14, X═Cl)

The procedure described in example 42 was repeated on same scale exceptthat after completion of the reaction, it was quenched withtriethylamine instead of water, and substantially the same results wereachieved. In this particular case, the final product5-{4-[2-chloro-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidenedione and its salt obtained was 1.3 g (62%), is identical in everyrespect with the product of example 42. m.p. 177° C.

EXAMPLE 505-{4-[2-Chloro-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidenedione (14, X═Cl)

To a solution of 25 g (0.067 mol) of5-{4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzyl}-2,4-thiazolidenedione dissolved in 250 mL chloroform was added 12 g (0.1008 mol) thionylchloride at reflux temperature in one hour. Reflux was continued forfurther one hour. Reaction mixture was cooled to 25° C. and added 100 mLwater. The mixture was washed with 10% Na₂CO₃ solution, organic layerwas separated; dried and concentrated under reduced pressure to obtain24.4 g (93%) of the titled product.

The product obtained was characterized by IR, Mass, ¹³C NMR, and ¹H NMR,which was found to be identical with the product obtained in example 42.

EXAMPLE 515-{4-[2-Chloro-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidenedione hydrochloride (14, X═Cl)

To a flask fitted with an overhead stirrer, a thermometer and acondenser was added a solution of 500 g (1.344 mol) of5-{4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzyl}-2,4-thiazolidenedione dissolved in 3500 mL chloroform. To this was added 146.3 mL (2.01mol) thionyl chloride dissolved in 500 mL chloroform at refluxtemperature in one hour. Reaction mixture was refluxed for further twohours. The solvent was evaporated and ether was added. Precipitated HClsalt was filtered and dried to get the titled product Yield of theproduct was 550.96 g (96%). map. 176-179° C.

The product obtained was characterized by IR, Mass, ¹³ C NMR and ¹H NMR,which was found to be identical with the hydrochloride salt of theproduct obtained in example 42.

EXAMPLE 525-{4-[2-Chloro-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidenedione hydrochloride (14, X═Cl)

The procedure described in example-51 was repeated on same scale exceptthat thionyl chloride was taken 191.9 g (1.6128 mol) and reactionmixture was refluxed for 30 hr. after complete addition of thionylchloride, the precipitated product was filtered off and dried.Substantially the same results were achieved. In this particular case,the final product5-{4-[2-chloro-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidenedione hydrochloride obtained was 522.27 g (91%), is identical in everyrespect with the HCl salt of example 42. m.p. 176-178° C.

EXAMPLE 535-{4-[2-Chloro-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidenedione (14, X═Cl)

To 50 g (0.1344 mol) of5-{4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzyl}-2,4-thiazolidenedione dissolved in 450 mL dichloromethane was added 19.5 mL (0.2679 mol)thionyl chloride dissolved in 50 mL chloroform at reflux temperature inone hour. Reflux was continued for two hours. Solvent was evaporated andether added into it. Precipitated solid was filtered off and dried toget 55 g (96%) of the titled product.

The product obtained was characterized by IR, Mass, ¹³C NMR and ¹H NMR,which was found to be identical with the product obtained in example 42.

EXAMPLE 545-{4-[2-Chloro-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidenedione hydrochloride (14, X═Cl)

To a stirred solution of 10 kg (26.88 mol) of5-{4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzyl}-2,4-thiazolidenedione dissolved in 70 lit. chloroform was added 4.818 Kg (40.32 mol)thionyl chloride dissolved in chloroform at reflux temperature. Reactionmixture was refluxed further. After suitable workup HCl salt wasprecipitated. Precipitated solid was filtered and dried to get thetitled product. Yield of the product was 10.9 kg (95%).

The product obtained was characterized by IR, Mass, ¹³C NMR, and ¹H NMR,which was found to be identical with the hydrochloride salt of theproduct obtained in example 42.

EXAMPLE 555-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidene dione(1)

To 5 g (0.0121 mol) of5-{4-[2-chloro-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidenedione dissolved in 25 mL acetic acid was added 1.62 (0.0243 mol) g zincin 5 min. Stirring continued for 15 hours at 25-30° C. Reaction mixturewas poured in excess water, made alkaline using 10% Na₂CO₃ and extractedwith ethyl acetate. After distilling off ethyl acetate in vacuo,methanol was added to precipitate out 1.13 g (25%) g of the crystallinesolid product. The two impurities identified in this reaction were5-ethyl-2-vinyl-pyridine 0.128 g (10%) and 5-(4-hydroxybenzyl)-thiazolidin-2,4-dione 0.342 g (12%).

The product obtained was characterized by IR, Mass, ¹³C NMR, and ¹H NMRwhich are as given below.

IR spectrum (cm⁻¹) 3417 (N—H str.), 1693, 1743 (C═O str.), 1037 (C—O—Cstr.) Mass spectrum (m/z) 357.1 (M + H)⁺ ¹³C-NMR (DMSO-d₆) δ 176.5,172.5, 157.8, 152.1, 145.9, 142.0, 141.1, 131.2, 129.9, 127.8, 115.2,66.2, 53.8, 37.0, 33.2, 25.4, 15.5 ¹H-NMR (DMSO-d₆) δ 12.0 (1H, s),6.84-8.71 (7H, m), 4.86 (1H, dd), 4.38 (2H, t), 3.48 (2H, t), 3.25 (1H,dd), 3.04 (1H, dd), 2.75 (2H, q), 1.21 (3H, t) Melting point 172-175° C.

The final product was dissolved into 12 mL methanol and 0.05 mL con. HClwas added into it at 25° C., Reaction mixture was refluxed for 30 min.and cooled to 10° C. Precipitated hydrochloride salt was filtered offand dried to yield 1.1 g (22%) of the salt, which was characterized byIR Mass, ¹³C NMR and ¹H NMR, which are as given below.

IR spectrum (cm⁻¹) 3257 (N—H str.), 1689, 1743 (C═O str.), 1155, 1244(C—O—C str.) Mass spectrum (m/z) 357.1 (M + H)⁺ ¹³C-NMR (DMSO-d₆) δ175.7, 171.7, 157.0, 151.0, 141.1, 129.0, 145.4, 139.8, 127.2, 130.4,114.4, 65.4, 53.0, 39.2, 36.2, 24.6, 14.6 ¹H-NMR (DMSO-d₆) δ 12.09 (1H,s), 6.82-8.7 (7H, m), 4.8 (1H, dd), 4.38 (2H, t), 3.5 (2H, t), 3.0 (2H,m), 2.75 (2H, q), 1.21 (3H, t) Melting point 190-193° C.

EXAMPLE 565-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidene dione(1)

The procedure described in example 55 was repeated except thattemperature was maintained 5-10° C., and substantially the same resultswere achieved. In this particular case, the final product5-{4-[2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl)-2,4-thiazolidene dioneobtained was 0.911 g (20%), is identical in every respect with theproduct of example 55. m.p. 172° C.

EXAMPLE 575-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidene dione(1)

To a solution of 0.8 g (0.00184 mol) of5-{4-[2-chloro-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidenedione dissolved in 10 mL ethyl acetate was added 0.8 mL (0.014 mol)acetic acid and 0.119 g (0.00184 mol) zinc in 5 minutes at 25-30° C.stirring continued for 9 hr. at 30-35° C. Solid material separated wasfiltered off and dried to get titled compound. Yield of the product was0.3 g (41%). map. 173° C.

The product obtained was characterized by IR, Mass, ¹³C NMR, and ¹H NMR,which was found to be identical with the product obtained in example 55.The impurity profile was also similar to the product obtained in example55.

EXAMPLE 585-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidene dione(1)

The procedure described in example 57 was repeated except that aceticacid was replaced by 1.038 g (0.014 mol) propionic acid, andsubstantially the same results were achieved. In this particular case,the final product5-{4-[2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidene dioneobtained was 0.3 g (41%), is identical in every respect with the productof example 55. m.p. 172° C.

EXAMPLE 595-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidene dione(1)

The procedure described in example 57 was repeated except thattetrahydrofuran was used as solvent, and substantially the same resultswere achieved. In this particular case, the final product5-{4-[2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidene dioneobtained was 0.13 g (18%), is identical in every respect with theproduct of example 55. m.p. 173° C.

EXAMPLE 605-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidene dione(1)

To a mixture of 5 ant 35% Con. HCl and 5 mL water, 0.5 g (0.0012 mol) of5-{4-[2-chloro-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidenedione was added followed by the addition of 0.039 g (0.0006 mol) zinc(tlc). Reaction mixture was poured into 20 mL water, made alkaline by10% K₂CO₃ solution and product was extracted with 25 mL ethyl acetate.Organic layer was separated, dried (magnesium sulfate) and concentratedunder reduced pressure. Methanol was added to the residual mass to get0.1 g (22%) crystalline titled product. m.p, 174° C.

The product obtained was characterized by IR, Mass, ¹³C NMR, and ¹H NMR,which was found to be identical with the product obtained in example 55.

EXAMPLE 615-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidene dione(1)

To a mixture of 35 mL ethanol and 7 mL (0.122 mol) glacial acetic acidwas dissolved 3.5 g (00084 mol) of5-{4-[2-chloro-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidenedione followed by addition of 0.819 g (0.0126 mol) zinc. Precipitatedproduct was filtered and dried to yield 1.91 g (60%) product. m.p. 174°C.

The product obtained was characterized by IR, Mass, ¹³C NMR and ¹H NMR,which was found to be identical with the product obtained in example 55.

EXAMPLE 625-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidene dione(1)

Into 10 mL (0.175 mol) glacial acetic acid, 1 g (0.0024 mol) of5-{4-[2-chloro-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidenedione and 100 mg (0.0018 mol) ammonium chloride were dissolved. Understirring 0.078 g (0.0012 mol) zinc was added. Subsequent work-up inwater yielded 0.6 g (66%) of the desired product. m.p, 175° C.

The product obtained was characterized by IR, Mass, ¹³ C NMR, and ¹H NMRwhich was found to be identical with the product obtained in example 55.

EXAMPLE 635-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidene dione(1)

The procedure described in example 61 was repeated on 5 g scale exceptthat isopropyl alcohol was used as solvent and reaction mixture wasallowed to stir for 8 hours. Substantially the same results wereachieved. In this particular case, the final product5-{4-[2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidene dioneobtained was 3 g (66%), is identical in every respect with the productof example 55. m.p. 174° C.

EXAMPLE 645-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidene dione(1)

0.63 g (0.0097 mol) Zinc dust and 8.93 mL (0.0582 mol) tetramethylethylenediamine were added into 80 mL ethanol under nitrogen atmosphere.To this a mixture of 1.18 mL acetic acid and 7.8 g (0.0194 mol)) of5-{4-[2-chloro-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidenedione dissolved in 16 mL ethanol was added in 15 min, at 5-10° C.Reaction mixture was allowed to achieve 27° C. and 4.74 mL acetic acidwas added in 15 minutes. Reaction mixture was stirred for 15 hr. Theproduct precipitated was filtered off and dried to obtain 3.98 g (56%)of the titled product. m.p. 173° C.

The product obtained was characterized by IR, Masse ¹³C NMR, and ¹H NMR,which was found to be identical with the product obtained in example 55.

EXAMPLE 655-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidene dione(1)

To a mixture of 40 mL ethanol and 10 mL propionic acid, 5 g (0.0117 mol)of5-{4-[2-chloro-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidenedione hydrochloride was dissolved. To this was added 1.5 g (0.0234 mol)of zinc and stirred. Reaction mixture was stirred for 12 hr. Productprecipitated was filtered off and dried to yield 2 g (48%) of the titledproduct. m.p. 175° C.

The product obtained was characterized by IR, Mass, ¹³C NMR, and ¹H NMR,which was found to be identical with the product obtained in example 55.

EXAMPLE 665-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidene dione(1)

70 g (0.150 mol) of5-{4-[2-chloro-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidenedione dissolved in a mixture methanol and acetic acid. To this was added21.85 g (0.3 mol) of and stirred. Product precipitated was filtered offand dried to get 51 g (80%) of the desired product. The impurity profilein this reaction was similar to the impurity profile described inexample 55. m.p. 174° C.

The product obtained was characterized by IR, Mass, ¹³C NMR and ¹H NMR,which was found to be identical with the product obtained in example 55.

The final product obtained above was treated with cone, HCl inisopropanol, Precipitated hydrochloride salt was filtered off and driedto yield 50 g of the salt, which was characterized by IR, Mass, ¹³C NMRand ¹H NMR, which was found identical with hydrochloride salt obtainedin example 55. m.p. 194-197° C.

EXAMPLE 675-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidene dione(1)

A solution of 250 g (0.5854 mol) of5-{4-[2-chloro-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidenedione hydrochloride in methanol and 500 mL (8.75 mol) acetic acid wasadded into a flask fitted with an overhead stirrer and a thermometer. Tothis was added 76.54 g (1.17 mol) of and stirred. The productprecipitated was filtered and dried. Yield of the product was 100 g(48%). The impurity profile in this reaction was similar to the impurityprofile described in example 55. m.p. 175° C.

The product obtained was characterized by IR, Mass, ¹³C NMR, and ¹H NMRwhich was found to be identical with the product obtained in example 55.

The final product treated with conc. HCl in ethanol. Precipitatedhydrochloride salt was filtered off and dried to yield 100 g of thesalt, which was characterized by IR, Mass, ¹³C NMR and ¹H NMR, which wasfound identical with hydrochloride salt obtained in example 55. map.192° C.

EXAMPLE 685-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidene dione 1)

10 kg (23.42 mol) of5-{4-[2-chloro-2-(5-ethylpyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidenedione hydrochloride was dissolved in a mixture of 80 lit. methanol and20 lit. acetic acid. To this was added 3.06 kg (46.8 mol) of zinc andstirred (tlc), Product precipitated was filtered off and dried to get7.5 Kg of the desired product. m.p. 172° C.

The product obtained was converted into its hydrochloride salt asdescribed in example 67 to obtain 7.72 Kg (84%) of the salt, which wasfound to be identical in all respect with the salt obtained in example55. The impurity profile in this reaction was similar to the impurityprofile described in example 55, m.p. 192° C.

EXAMPLE 695-{4-[2-(5-Ethyl-pyridin-2-yl)-2-mesyl-ethoxy]-benzylidene}-2,4-thiazolidenedione (13, X═OMs)

A mixture of 5 g (0.0135 mol) of5-{4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzylidene}-2,4-thiazolidenedione and 1.63 g (0.0162 mol) triethyl amine was suspended in 50 mLdichloromethane and cooled to 0-5° C. To this was added 1.5 g (0.0135mol) of mesyl chloride dissolved in 10 mL dichloromethane at 0-5° C.Reaction mixture was stirred for 2 hr. Subsequent work-up in excesswater gave crude 3 g product, which was purified by columnchromatography to get the titled product. Yield of the product was 4.54g (75%).

The product obtained was characterized by IR, Mass and ¹H NMR, which areas given below.

IR spectrum (cm⁻¹) 1739, 1701 (C═O str.), 1342 (S═O str.) Mass spectrum(m/z) 449.1 (M + H)⁺ ¹H-NMR (DMSO-d₆) δ 12.3 (1H, s), 7.8 (1H, s),6.95-7.74 (7H, m), 5.99 (1H, dd), 4.54 (2H, m), 3.1 (3H, s), 2.68 (2H,q), 1.27 (3H, t) Melting point 60-65° C.

EXAMPLE 705-{4-[2-(5-Ethyl-pyridin-2-yl)-2-mesyl-ethoxy]-benzyl}-2,4-thiazolidenedione (14, X═OMs)

To a suspension of 1 g (0.0022 mol) of5-{4-[2-(5-ethyl-pyridin-2-yl)-2-mesyl-ethoxy]-sbenzylidene}-2,4-thiazolidene dione in 10 mL aq. methanol was added 0.5g of 10% palladium charcoal. Reaction mixture was subjected tohydrogenation in Parr apparatus for 14 hr. at 60 psi. After subsequentwork up 0.3 g crude product obtained, which was purified to get thedesired product. Yield of the product was 0.22 g (22%).

The product obtained was characterized by Mass and ¹H NMR, which are asgiven below.

Mass spectrum (m/z) 451.1 (M + H)⁺ ¹H-NMR (DMSO-d₆) δ 12.2 (1H, s),6.8-8.4 (7H, m), 5.6 (1H, dd), 4.13 (1H, dd), 4.54 (2H, m), 3.4 (2H, m),3.1 (3H, s), 2.68 (2H, q), 1.2 (3H, t)

EXAMPLE 715-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidene dione(1)

1 g (0.0022 mol) of5-{4-[2-(5-ethyl-pyridin-2-yl)-2-mesyl-ethoxy]-benzyl}-2,4-thiazolidenedione was added into 10 mL acetic acid. To this was added 0.246 gm(0.0066 mol) sodium borohydride at 40-45° C. in 5 min. Reaction mixturewas stirred for 15 hr. at 40-45° C. After subsequent work up crudeproduct was obtained which yielded the titled product afterpurification, Yield of the product was 0.079 g (10%).

The product obtained was characterized by IR Mass, ¹³C NMR, and ¹H NMR,which was found to be identical with the product obtained in example 55.

EXAMPLE 725-{4-[2-(5-Ethyl-pyridin-2-yl)-2-mesyl-ethoxy]-benzyl}-2,4-thiazolidenedione (14, X═OMs)

1.63 g (0.0161 mol) triethyl amine was added to a mixture of 5 g (0.0134mol) of5-{4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzyl}-2,4-thiazolidenedione and 1.538 g (0.0134 mol) of mesyl chloride in 60 mLdichloromethane at 0° C. Reaction mixture was stirred for 2 hr. Theprogress of reaction was monitored on TLC and after completion ofreaction, subsequent work-up in excess water and purification of thecrude product yielded 4.23 g (70%) of the desired product.

The product obtained was characterized by IR, Mass) ¹³C NMR and ¹H NMR,which was found to be identical with the product obtained in example 70.

EXAMPLE, 735-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidene dione(1)

To 1 g (0.0022 mol) of5-{4-[2-(5-ethyl-pyridin-2-yl)-2-mesyl-ethoxy]-benzylidene}-2,4-thiazolidenedione suspended in 7 mL water was added a dissolved mixture of 0.13 g(0.0011 mol) dimethylglyoxime and 0.053 g (0.00022 mol) cobaltouschloride hexahydrate in 2 mL DMF at 65-70° C. To this 0.34 g (0.0092mol) of sodium borohydride dissolved in 5 mL of water was added dropwise. Reaction mixture was stirred at 60-65° C. for 3 hrs. Subsequentwork-up which involved addition of water, extraction of the product withethyl acetate, concentrating ethyl acetate in vacuo yielded whitedesired product. Yield of the product was 0.119 g (15%).

The product obtained was characterized by IR, Mass, ¹³C NMR, and ¹H NMR,which was found to be identical with the product obtained in example 55.

EXAMPLE 745-{4-[2-(5-Ethyl-pyridin-2-yl)-2-tosyl-ethoxy]-benzylidene}-2,4-thiazolidenedione (13, X═OTs)

1.63 g (0.0161 mol) triethylamine was added to a stirred solution of 5 g(0.0135 mol) of5-(4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzylidene)-2,4-thiazolidenedione and 2.57 g (0.0135 mol) of tosyl chloride dichloromethane wasadded and cooled at 0° C. Reaction mixture was stirred for 2 hr.Progress of the reaction was monitored by TLC and after completion ofthe reaction, subsequent work-up in excess water gave crude product,which was purified to obtain the titled product. Yield of the productwas 5.66 g (80%).

The product obtained was characterized by Mass and ¹H NMR, which are asgiven below.

Mass spectrum (m/z) 525 (M + H)⁺ ¹H-NMR (DMSO-d₆) δ 12.4 (1H, s), 7.1(1H, s), 6.85-8.48 (11H, m), 5.5 (1H, dd), 4.5 (2H, m), 2.68 (2H, q),2.38 (3H, s), 1.2 (3H, t)

EXAMPLE 755-{4-[2-(5-Ethyl-pyridin-2-yl)-2-tosyl-ethoxy]-benzyl}-2,4-thiazolidenedione (14, X═OTs)

To 1 g (0.0019 mol) of5-{4-[2-(5-ethyl-pyridin-2-yl-)-2-tosyl-ethoxy]-benzylidene}-2,4-thiazolidenedione suspended in 10 mL aq. methanol was added 0.5 g of 10% palladiumcharcoal. Reaction mixture was subjected to hydrogenation in Parrapparatus for 14 hr. at 60 psi. After subsequent work up andpurification led to 0.2 g (20%) of the desired product. Furtherreduction of product to 1 was also observed 0.135 g (20%).

The product obtained was characterized by Mass and ¹H NMR, which are asgiven below.

Mass spectrum (m/z) 527.1 (M + H)⁺ ¹H-NMR (DMSO-d₆) δ 12.3 (1H, s),6.8-8.4 (11H, m), 5.65 (1H, dd), 4.6 (1H, dd), 4.4 (2H, m), 3.34 (2H,m), 2.64 (2H, q), 2.4 (3H, s), 1.19 (3H, t)

EXAMPLE 765-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidene dione(1)

Into 10 mL acetic acid, 1.167 g (0.0022 mol) of5-{4-[2-(5-ethyl-pyridin-2-yl)-2-tosyl-ethoxy]-benzyl}-2,4-thiazolidenedione and 0.246 g (0.0066 mol) sodium borohydride were added at 40-45°C. Reaction mixture was stirred for 15 hr. at 40-45° C. After subsequentwork up crude product was obtained which yielded the titled productafter purification. Yield of the product was 0.039 g (5%).

The product obtained was characterized by IR, Mass, ¹³C NMR, and ¹H NMR,which was found to be identical with the product obtained in example 55.

EXAMPLE 775-{4-[2-(5-Ethyl-pyridin-2-yl-2-tosyl-ethoxy]-benzyl}-2,4-thiazolidenedione (4, X═OTs)

1.56 g (0.0154 mol) triethylamine was added to a solution of 5 g (0.0134mol) of5-{4-[2-(5-ethyl-pyridin-2-yl-)-2-hydroxy-ethoxy]-benzyl}-2,4-thiazolidenedione and 2.55 g (0.0134 mol) of tosyl chloride dichloromethane at 0°C., Reaction mixture was stirred for 2 hr. Progress of the reaction wasmonitored by TLC and after completion of the reaction, subsequentwork-up in excess water and purification of the crude product yielded5.30 g (75%) of the desired product.

The product obtained was characterized by IR, Mass, ¹³C NMR and ¹H NMR,which was found to be identical with the product obtained in example 75.

EXAMPLE 785-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidene dione(1)

To 1 g (0.0019 mol) of5-{4-[2-(5-ethyl-pyridin-2-yl-)-2-tosyl-ethoxy]-benzylidene}-2,4-thiazolidenedione suspended in 7 mL water was added a dissolved mixture of 0.11 g(0.001 mol) dimethylglyoxime and 0.045 g (0.00018 mol) cobaltus chloridehexahydrate in 2 mL DMF at 65-70° C. To this 0.29 g (0.0078 mol) ofsodium borohydride in 5 mL of water was added drop wise. Reactionmixture was stirred at 60-65° C. for 3 hr. Progress of the reaction wasmonitored by TLC and after completion of reaction, the work-up involvedaddition of excess of water, extraction of the product with ethylacetate, removal of the organic solvent in vacuo which yielded 0.04 g(6%) of the crystalline product.

The product obtained was characterized by IR, Mass, ¹³C NMR, and ¹H NMR,which was found to be identical with the product obtained in example 55.

EXAMPLE 795-{4-[2-Chloro-2-(5-ethyl-pyridine-2-yl)-ethoxy]-benzylidene}-2,4-thiazolidenedione (13, X═Cl)

To a stirred solution of 5 g (0.0135 mol) of5-(4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzylidene)-2,4-thiazolidenedione dissolved in 40 mL chloroform was added 1.47 ml (0.02 mol) thionylchloride dissolved in 2 mL chloroform at reflux temperature in one hour.Reflux was continued for further two hour. Chloroform was distilled outether was added into it. Precipitated solid was filtered off and driedto obtain 4.5 g (86%) of the desired product.

The product obtained was characterized by IR, Mass, ¹³C NMR, and ¹H NMR,which are as given below,

IR spectrum (cm⁻¹) 3409 (N—H str.), 1689, 1735 (C═O str.), 1043 (C—O—Cstr.) Mass spectrum (m/z) 389 (M + H)⁺ ¹³C-NMR (DMSO-d₆) δ 167.9, 167.4,159.2, 150.2, 144.3, 142.5, 142.2, 132.1, 131.6, 126.3, 124.9, 120.8,115.6, 69.5, 56.1, 25.0, 14.8 ¹H-NMR (DMSO-d₆) δ 11.18 (1H, s),7.08-8.69 (7H, m), 7.6 (1H, s), 5.85 (1H, t), 4.76 (2H, d), 2.71 (2H,q), 1.15 (3H, t) Melting point 177-181° C.

EXAMPLE 805-{4-[2-Chloro-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidenediode (14, X═Cl)

To a stirred solution of 1 g (0.0026 mol) of5-{4-[2-chloro-2-(5-ethyl-2-pyridyl)-ethoxy]-benzylidene}-2,4-thiazolidenedione dissolved in 10 mL aq. methanol was added 0.5 g 10% Pd/C. Reactionmixture was subjected to hydrogenation in Parr apparatus for 16 hr. at60 psi pressure, After subsequent work-up and purification furnishedtitled product. Yield of the product was 0.29 g (29%). Further reductionof product to 1 was also observed 0.09 g (10%).

The product obtained was characterized by IR, Mass, ¹³C NMR and ¹H NMR,which was found to be identical with the product obtained in example 42and example 55.

EXAMPLE 815-{4-[2-Chloro-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidenedione (14, X═Cl)

To a stirred solution of 1 g (0.0026 mol) of5-{4-[2-chloro-2-(5-ethyl-2-pyridyl)-ethoxy]-benzylidene}-2,4-thiazolidenedione dissolved in 10 red tetrahydrofuran was added 1 g Raney —N₁ and H₂gas was passed through reaction mixture for 12 hr. After subsequentwork-up and purification titled product was obtained. Yield of theproduct was 0.40 g (40%). Further reduction of product to 1 was alsoobserved. 0.073 g (8%).

The product obtained was characterized by IR, Mass, ¹³C NMR and ¹H NMRwhich was found to be identical with the product obtained in example 42and example 55.

EXAMPLE 825-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidene dione(1)

In a mixture of 8 mL methanol and 2 mL (0.035 mol) acetic acid, 1 g(0.0025 mol) of5-{4-[2-chloro-2-(5-ethyl-2-pyridyl)-ethoxy]-benzyl}-2,4-thiazolidenedione was dissolved. To this was added 0.33 g (0.005 mol) Zinc at 25-30°C. Reaction mixture was stirred for 15 hr., precipitated product wasfiltered and dried to get 0.3 g (33%) of the titled product.

The product obtained was characterized by IR, Mass, ¹³C NMR and ¹H NMR,which was found to be identical with the product obtained hi example 55.

EXAMPLE 835-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidene dione(1)

A mixture of 0.15 g (0.0013 mol) dimethylglyoxime and 0.061 g (0.0002mol) CoCl₂. 6H₂O in 2 mL of DMF was added to a suspension of 1 g (0.0026mol) of5-{4-[2-chloro-2-(5-ethyl-2-pyridyl)-ethoxy]-benzylidene}-2,4-thiazolidenedione in 7 mL of water at 65-70° C. followed by drop wise addition of0.399 g (0.0107 mol) sodium borohydride. After complete addition ofsodium borohydride reaction mixture was stirred at 65-70° C. for 4 hrs.Product was extracted with methyl tert-butyl ether. After concentratingsolvent up to 90%, 20 mL cyclohexane was added to the reaction mixturewith stirring. The product precipitated was filtered off and dried.Yield of the product was 0.054 g (6%).

The product obtained was characterized by IR, Mass, ¹³C NMR, and ¹H NMR,which was found to be identical with the product obtained in example 55.

EXAMPLE 845-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzylidene}-2,4-thiazolidenedione (13, X═H)

In a mixture of 8 mL methanol and 2 mL (0.035 mol) acetic acid, 1 g(0.0025 mol) of5-{4-[2-chloro-2-(5-ethyl-2-pyridyl)-ethoxy]-benzylidene}-2,4-thiazolidenedione was dissolved. To this was added 0.33 g (0.005 mol) Zinc at 25-30°C. Reaction mixture was stirred for 15 hr., precipitated product wasfiltered off and dried to yield 0.55 g (60%) of the titled product.

The product obtained was characterized by comparison with a referencesample prepared by a known method (see prior art).

EXAMPLE 855-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidene dione(1)

To a solution of 1 g (0.0028 mol) of5-(4-[2-(5-ethyl-2-pyridyl)-ethoxy]-benzylidene)-2,4-thiazolidene dionedissolved in 10 mL aq. methanol was added 0.5 g 10% Pd/C. Reactionmixture was subjected to hydrogenation in Parr apparatus for 16 hr. at60 psi. Progress of the reaction was monitored by TLC and aftercompletion of the reaction, subsequent work-up furnished the titledproduct. Yield of the product was 0.35 g (35%).

The product obtained was characterized by IR, Mass, ¹³C NMR, and ¹H NMR,which was found to be identical with the product obtained in example 55.

EXAMPLE 86 2-Bromo-[5-ethyl-pyridin-2-yl]-ethyl bromide (3, X═Br)

To a cooled solution (0-5° C.), of 3 g (0.0221 mol) of-5-ethyl-2-vinyl-pyridine dissolved in 50 mL carbon tetrachloride wasadded 1.13 mL (0.0221 mol) bromine in 10 mL CCl₄ drop wise. Reactionmixture was stirred for 2 hr. After concentrating CCl₄ under reducedpressure 2.84 g (43%) titled product was obtained.

The product obtained was characterized by Mass and ¹H NMR, which are asgiven below.

Mass spectrum (m/z) 294 (M + H)⁺ ¹H-NMR (DMSO-d₆) δ 7.9-8.6 (3H, m), 5.9(1H, dd), 4.20-4.45 (2H, m), 2.8 (2H, q), 1.3 (3H, t)

EXAMPLE 87 4-[2-Bromo-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzaldehyde (9,X═Br)

To a stirred solution of 0.67 g (0.0055 mol) p-hydroxy benzaldehyde and0.237 g (0.0098 mol) sodium hydride in 10 mL DMF, 1 g (0.0034 mol)2-bromo-[5-ethyl-2-pyridyl]-ethyl bromide dissolved in 10 mL of Do wasadded at 10-15° C. Reaction mixture was stirred for 1 hr at 25-30° C.and further warmed at 75-80° C. for 24 br. After subsequent work-upcrude product was obtained which on purification gave titled compound,Yield of the product was 0.068 g (6%). The product obtained wascharacterized by satisfactory mass.

EXAMPLE 88 2-(5-Ethyl-1-oxy-pyridin-2-yl)-ethanol (16)

To a solution of 100 g (0.655 mol) 2-(5-ethyl-pyridin-2-yl)-ethanol in500 mL acetic acid was added 118 g (1.049 mol) 30% hydrogen peroxide at25-30° C. Reaction mixture was refluxed at 100° C. (tlc) for 14 hr.After completion of the reaction acetic acid was removed under vacuum,and the residual mass was poured in excess water and made alkaline by10% Na₂CO₃ solution. Product was extracted with ethyl acetate and afterconcentrating ethyl acetate in vacuo, 89.58 g (81%) crystalline productwas obtained.

The product obtained was characterized by Mass ¹³C NMR, and in ¹H NMR,which are as given below,

Mass spectrum (m/z) 168.1 (M + H)⁺ ¹³C-NMR (CDCl₃) δ 170.7, 148.2,138.7, 135.9, 125.8, 62.0, 34.2, 25.5, 14.4 ¹H-NMR (CDCl₃) δ 7.07-8.14(3H, m), 5.7 (1H, broad s), 3.9 (2H, t), 3.2 (2H, t), 2.6 (2H, q), 1.2(3H, t)

EXAMPLE 89 Acetic Acid 2-acetoxy-2-(5-ethyl-1-pyridin-2-yl)-ethyl Ester(17)

14.6 g (0.14 mol) Acetic anhydride was added to 20 g (0.11 mol) of2-(5-ethyl-1-oxy-pyridin-2-yl)-ethanol. Reaction mixture was heated at120° C. for 30 min. Reaction mixture was quenched with water and productwas extracted with ethyl acetate. Ethyl acetate was dried andconcentrated under reduced pressure to get the crude product which afterpurification gave acetic acid 2-acetoxy-2-(5-ethyl-1-pyridin-2-yl)ethylester, Yield of the product was 7.81 g (26%).

The product obtained was characterized by IR, Mass, ¹³C NMR, and ¹H NMR,which are as given below.

IR spectrum (cm⁻¹) 1741 (C═O str.), 1047 (C—O—C str.) Mass spectrum(m/z) 252.1 (M + H)⁺ ¹³C-NMR (DMSO-d₆) δ 170.3, 169.9, 152.9, 149.0,138.8, 135.8, 121.2, 73.6, 64.9, 29.4, 25.5, 20.8, 14.9 ¹H-NMR (DMSO-d₆)δ 7.28-8.44 (3H, m), 6.0 (1H, dd), 4.43-4.58 (2H, m), 2.6 (2H, q), 2.1(3H, s), 2.0 (3H, s), 1.2 (3H, t)

EXAMPLE 90 1-(5-Ethyl-pyridin-2-yl)-ethan-1,2-diol (11)

19.91 g (0.497 mol) Sodium hydroxide was added to a solution of 71 g(0.226 mol) acetic acid 2-acetoxy-2-(5-ethyl-pyridin-2-yl)-ethyl esterin 355 mL water. Reaction mixture was stirred at 40° C. for 2 hr. Aftercompletion of reaction on TLC, reaction mixture was neutralized withcon. HCl and precipitated solid was filtered off and dried to get1-(5-ethyl-pyridin-2-yl)-ethan-1,2-diol, Yield of the product was 32.1 g(68%).

The product obtained was characterized by IR, Mass, ¹³C NMR, and ¹H NMR,which are as given below,

IR spectrum (cm⁻¹) 3400-3500 (O—H str.), 2875-2972 (C—H str.) Massspectrum (m/z) 168.1 (M + H)⁺ ¹³C-NMR (CDCl₃) δ 170.1, 147.7, 138.4,136.4, 120.5, 73.2, 67.1, 25.6, 15.2 ¹H-NMR (CDCl₃) δ 7.27-8.34 (3H, m),4.9 (1H, m), 4.82 (2H, broad s), 3.71-3.94 (2H, m), 2.65 (2H, q), 1.25(3H, t)

EXAMPLE 91 5-Ethyl-2-[2-oxo-(1,3,2)-dioxathiolan-4-yl]-pyridine (10)

4.98 mL (0.0387 mol) triethylamine was added to a solution of 3 g (0.017mol) 1-(5-ethyl-pyridin-2-yl)-ethan-1,2-diol dissolved in 60 mLdichloromethane at 0-5° C. To this 1.43 mL (0.019 mol) thionyl chloridewas added drop wise in 15 min. and stirring was continued for 1 hr.Reaction mixture was quenched with 10% sodium bicarbonate solution.Product was extracted with dichloromethane, which was concentrated invacuo to obtain titled product. Yield of the product was 3.44 g (90%).

The product obtained was characterized by IR, Mass, ¹³C NMR and ¹H NMR,which are as given below.

IR spectrum (cm⁻¹) 1375, 1398 (O—SO₂ str.) Mass spectrum (m/z) 214.1(M + H)⁺ ¹³C-NMR (DMSO-d₆) δ 170.3, 149.0, 139.5, 136.5, 121.9, 84.3,81.2, 25.0, 14.0 ¹H-NMR (DMSO-d₆) δ 7.44-8.46 (3H, m), 6.0 (1H, t),4.69-5.10 (2H, m), 2.6 (2H, q), 2.1 (3H, s), 2.0 (3H, s), 1.1 (3H, t)

EXAMPLE 92 4-[2-(5-Ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde(9a)

0.5 g (0.0023 mol) 5-ethyl-2-(2-oxo-[1,3,2]-dioxathiolan-4-yl)-pyridinewas added into solution of 0.343 g (0.0027 mol) p-hydroxy benzaldehydedissolved in 5 mL DMF. Reaction mixture was heated at 80° C. for 14 hr.Subsequent work up furnished 0.3 g (47%) the desired product.

The product obtained was characterized by IR, Mass, ¹³C NMR and ¹H NMR,which was found to be identical with the product obtained in example 17.The impurity of regio isomer4-[1-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde as describedin example 17 was also obtained 0.2 g (31%).

EXAMPLE 93 4-[2-Chloro-2-(5-ethyl-2-pyridyl)-ethoxy]-benzaldehyde (9,X═Cl)

To a stirred solution of 5 g (0.018 mol)4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde dissolved inchloroform was added 2.63 g (0.022 mol) thionyl chloride at 55-60° C.Reaction mixture was refluxed for 1 hr. Progress of the reaction wasmonitored by TLC and after completion of reaction, subsequent work-up inalkaline water yielded 4 g (75%) of the desired product.

The product obtained was characterized by Mass, ¹³C NMR and ¹H NMR,which are as given below.

Mass spectrum (m/z) 290.1 (M + H)⁺ ¹³C-NMR (DMSO-d₆) δ 190.5, 162.9,153.5, 149.2, 139.3, 136.2, 131.4, 130.2, 122.4, 114.8, 71.0, 59.5,25.6, 15.0 ¹H-NMR (DMSO-d₆) δ 9.8 (1H, s), 6.91-8.45 (7H, m), 5.29 (1H,dd), 4.72 (1H, dd), 4.56 (1H, dd), 2.65 (2H, q), 1.24 (3H, t)

EXAMPLE 94 4-[2-Bromo-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzaldehyde (9,X═Br)

2.93 g (0.01 mol) PBr₃ was added to a solution of 5 g (0.018 mol)4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde dissolved in50 mL chloroform at 55-60° C. Reaction mixture was refluxed for 1 hr.Progress of the reaction was monitored by TLC and after completion ofreaction, subsequent work-up in alkaline water furnished 3 g (50%) ofdesired product.

EXAMPLE 955-{4-[2-Chloro-2-(5-ethyl-pyridin-2-yl)ethoxy]-benzylidene}-2,4-thiazolidinedione (13, X═Cl)

A mixture of 2 g (0.017 mol) thiazolidin-2,4-dione, 2 g (0.034 mol)acetic acid and 3 g (0.03 mol) piperidine were added to a solution of 5g (0.017 mol) 4-[2-chloro-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzaldehydedissolved in 50 mL toluene. Reaction mixture was heated and water wasremoved azeotropically. After completion of the reaction on TLC, toluenewas distilled out completely under reduced pressure. Product was pouredinto excess of water and extracted with ethyl acetate. Afterconcentrating ethyl acetate in vacuo and making its HCl salt in usualway 4.3 g (60%) desired product obtained.

The product obtained was characterized by IR, Mass, ¹³C NMR and ¹H NMR,which are as given in example 79.

EXAMPLE 965-{4-[2-Bromo-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzylidene}-2,4-thiazolidinedione (13, X═Br)

To stirred solution of 5 g (0.015 mol)4-[2-bromo-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzaldehyde dissolved in 50ml, toluene was added 1.85 g (0.015 mol) thiazolidin-2,4-dione followedby addition of 2 g (0.03 mol) acetic acid and 3 g (0.03 mol) piperidine.Reaction mixture was heated and water was removed azeotropically. Aftercompletion of the reaction on TLC, toluene was distilled out completelyunder reduced pressure. Product was poured into excess of water andextracted with ethyl acetate. On concentrating ethyl acetate in vacuo,0.65 g (10%) desired product obtained with satisfactory mass. The ¹H NMRwas similar to the ¹H NMR of example 79.

EXAMPLE 97 4-[2-(5-Ethyl-pyridin-2-yl)-2-mesyl-ethoxy]-benzaldehyde (9,X═OMs)

0.89 g (0.0088 mol) triethyl amine was added to a solution of 0.2 g(0.0007 mol) 4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehydeand 0.098 g (0.0008 mol) mesyl chloride dissolved in 5 mLdichloromethane at 0-5° C. Reaction mixture was stirred at 0-5° C. for 4hr. Progress of the reaction was monitored by TLC and after completionof reaction, substantial work-up in excess water yielded 0.8 g (70%) ofthe desired product. The product obtained was characterized by Mass andin NMR, which are as given below.

Mass spectrum (m/z) 350.2 (M + H)⁺ ¹H-NMR (DMSO-d₆) δ 9.8 (1H, s),7.15-8.48 (7H, m), 5.98 (1H, t), 4.58 (2H, d), 3.25 (3H, s), 2.65 (2H,q), 1.19 (3H, t)

EXAMPLE 985-{4-[2-(5-Ethyl-pyridin-2-yl)-2-mesyl-ethoxy]-benzylidene}-2,4-thiazolidinedione (13, X═OMs)

To a stirred solution of 0.65 g (0.0018 mol)4-[2-(5-ethyl-pyridin-2-yl)-2-mesyl-ethoxy]-benzaldehyde dissolved in 10mL toluene was added 0.211 g (0.0018 mol) thiazolidin-2,4-dione followedby addition of 0.161 g (0.03 mol) acetic acid and 0.228 g (0.03 mol)piperidine. Reaction mixture was refluxed at 120-130° C. for 4 hr. Aftercompletion of reaction on TLC, subsequent work-up gave the titledproduct. Yield of the product was 0.24 g (29%). The product obtained wasidentical to the product obtained in example 69.

EXAMPLE 99 4-[2-(5-Ethyl-pyridin-2-yl)-2-tosyl-ethoxy]-benzaldehyde (9,X═OTs)

0.44 g (0.0044 mol) triethyl amine was added to a solution of 1 g(0.0036 mol) 4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehydeand 0.7 g (0.0036 mol) tosyl chloride dissolved in 25 mL dichloromethaneat 0-5° C. Reaction mixture was stirred at 0-5° C. for 4 hr. Progress ofthe reaction was monitored by TLC and after completion of reaction,substantial work-up in excess water yielded the desired product. Yieldof the product was 1 g (70%).

The product obtained was characterized by Mass and ¹H NMR, which are asgiven below.

Mass spectrum (m/z) 426.2 (M + H)⁺ ¹H-NMR (DMSO-d₆) δ 9.87 (1H, s),6.76-8.38 (11H, m), 5.84 (1H, dd), 4.37-4.49 (2H, dd), 2.66 (2H, q),2.40 (3H, s), 1.26 (3H, t)

EXAMPLE 1005-{4-[2-(5-Ethyl-pyridin-2-yl)-2-tosyl-ethoxy]-benzylidene}-2,4-thiazolidinedione (13, X═OTs)

To 1 g (0.0023 mol)4-[2-(5-ethyl-pyridin-2-yl)-2-tosyl-ethoxy]-benzaldehyde dissolved in 15mL toluene was added 0.27 g (0.0023 mol) thiazolidin-2,4-dione. To this0.21 g (0.0035 mol) acetic acid and 0.3 g (0.0035 mol) piperidine wereadded, Reaction mixture was refluxed at 120-130° C. for 4 hr. Aftercompletion of reaction on TLC, substantial work-up gave the titledproduct. Yield of the product was 0.36 g (30%).

The product obtained was identical to the product obtained in example74.

EXAMPLE 1015-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidene dione(1)

In a mixture of 8 mL methanol and 2 mL (0.035 mol) acetic acid, 5 g(0.0115 mol) of5-{4-[2-chloro-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-2,4-thiazolidinedione was dissolved and to this under stirring was added 0.3 g (0.0046mol) zinc at 25-30° C. and stirring was continued for 14 hours. Reactionmixture was poured in access water, made alkaline using 10% Na₂CO₃ andextracted with ethyl acetate. Ethyl acetate was dried (magnesiumsulfate) and concentrated in vacuo. Methanol was added to the residualmass obtained which led to the formation of the desired product. Yieldof the product was 2.05 g (45%). m.p. 173° C.

The product obtained was characterized by IR, Mass, ¹³C NMR, and ¹H NMR,which was found to be identical with the product obtained in example 17.

Pharmaceutical compositions containing the novel compounds 13 and 14 ortheir salts, of the present invention may be prepared by conventionaltechniques as are well known in the art, e.g. as described in Remington:the Science and Practice of Pharmacy, 19^(th) Ed., 1995. Thecompositions may be in the conventional forms, such as capsules,tablets, powders, solutions, suspensions, syrups, aerosols or topicalapplications. They may contain suitable solid or liquid carriers or insuitable sterile media to form injectable solutions or suspensions. Thecompositions may contain 0.5 to 20%, preferably 0.5 to 10% by weight ofthe active compound, the remaining being pharmaceutically acceptablecarriers, excipients, diluents, solvents and the like as are well known.

The novel compounds 13 & 14 or their salts, in addition to being usefulas intermediates for the preparation of thiazolidinediones of formula 1,are also useful for the treatment and/or prophylaxis of disease causedby metabolic disorders such as hyperlipidemia, insulin resistance,hyperglycemia, obesity and the likes.

The novel compounds 13 & 14 or their salts, of the invention may beadministered to a mammal, especially, a human in need of such treatment,prevention, elimination, alleviation or amelioration of diseasesmentioned above.

In another aspect of the present invention, method of treatment and/orprevention of the diseases mentioned above are provided using the novelcompounds 13 & 14 or their salts, of the present invention.

The Novel Process to Manufacture Pioglitazone Described in the PresentInvention has the Following Advantages:

-   1. Less no of steps (4-6), especially the route 2 to 9 to 13 to 1 or    2 to 9 to 13 to 14 to 1.-   2. Describes several new and novel intermediates eg., 2, 3, 14, 3    and 6.-   3. Involves operational simplicity, as most of the intermediates    involved are solids.-   4. Offers opportunity to make cationic and protic salts, which will    offer further operational simplicity during manufacturing and    purification.-   5. Involves high yielding solution phase chemistry and mild reaction    conditions.-   6. Provides pure intermediates and final product, due to operational    simplicity and cleanliness of the reaction.-   7. The process avoids use of unpleasant smelling acrylate    derivatives and various other drawbacks mentioned in prior art.-   8. The synthetic route offers opportunity to integrate 2-3 steps    into one, thereby further enhancing operational simplicity.-   9. All the above factors contribute to the cost effectiveness of the    process and consequent better opportunities for commercialization.

We claim:
 1. A compound of formula 14 or its salt

wherein X is selected from the group consisting of OH, CI, Br, OMs, andOTs and R is selected from the group consisting of straight chain orbranched alkyl groups of one to six carbon atoms.
 2. The compound ofclaim 1 or its salt, wherein R is 5-ethyl.
 3. A pharmaceuticalcomposition comprises the compound as claimed in claim 1 or itspharmaceutically acceptable salt, with pharmaceutically acceptablecarrier, excipient, diluent or solvent.
 4. The compound of claim 1 orits salt, wherein R is selected from the group consisting of butyl,iso-butyl, sec-butyl, tert-butyl, pentyl, iso-pentyl, neo-pentyl, andhexyl.
 5. The compound of claim 1 or its salt, wherein R is selectedfrom the group consisting of methyl, ethyl, propyl, and iso-propyl.